Myriad factors and pathways influencing tumor radiotherapy resistance
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Lanjuan Mi
Abstract
Radiotherapy is a cornerstone in the treatment of various tumors, yet radioresistance often leads to treatment failure and tumor recurrence. Several factors contribute to this resistance, including hypoxia, DNA repair mechanisms, and cancer stem cells. This review explores the diverse elements that drive tumor radiotherapy resistance. Historically, resistance has been attributed to cellular repair and tumor repopulation, but recent research has expanded this understanding. The tumor microenvironment – characterized by hypoxia, immune evasion, and stromal interactions – further complicates treatment. Additionally, molecular mechanisms such as aberrant signaling pathways, epigenetic modifications, and non-B-DNA structures play significant roles in mediating resistance. This review synthesizes current knowledge, highlighting the interplay of these factors and their clinical implications. Understanding these mechanisms is crucial for developing strategies to overcome resistance and improve therapeutic outcomes in cancer patients.
1 Introduction
As cancer incidence and mortality rise globally, this disease poses a serious threat to human health, reducing life expectancy. According to the latest global cancer statistics from the World Health Organization and the International Agency for Research on Cancer, 19.3 million new cancer cases were reported in 2020, leading to nearly 10 million deaths. By 2040, cancer-related deaths could surge to 28.4 million [1,2]. In response, various strategies have been developed, including surgery, chemotherapy, radiotherapy, immunotherapy, and more [3]. Among these, radiotherapy has been a critical treatment modality since Marie Curie’s discovery of radioactivity [4,5].
The primary goal of ionizing radiotherapy is to control localized tumors by inducing DNA damage and apoptosis in cancer cells. High-energy photon radiation, such as X-rays and γ-rays, is typically used. Radiotherapy works through both direct and indirect mechanisms: it directly causes single-strand breaks (SSB) and double-strand breaks (DSB) in DNA, halting cell proliferation and leading to cell death, while indirectly producing reactive oxygen species (ROS) that amplify DNA damage in normoxic tissues (Figure 1). Technological advancements, such as intensity-modulated radiotherapy, stereotactic body radiotherapy (SBRT), image-guided radiotherapy, and proton therapy, have optimized radiation delivery and minimized collateral damage. However, challenges remain, particularly the enhanced DNA damage response (DDR) and tumor heterogeneity, which hinder the efficacy of radiotherapy as a stand-alone treatment [6,7,8]. Therefore, understanding the mechanisms behind tumor radiotherapy resistance is crucial.
Ionizing radiation (IR) mechanism in radiotherapy: IR directly damages DNA, leading to potential cell death or permanent growth arrest if the damage is not repaired. Indirectly, IR generates ROS through the radiolysis of water and oxygen in normoxic conditions, causing additional DNA damage. Under hypoxic conditions, ROS generation is reduced, diminishing DNA damage.
This article focuses on the cellular and molecular factors contributing to tumor radiotherapy resistance and outlines future research directions based on these factors.
2 DNA repair mechanisms and cell cycle
2.1 Overview of DNA damage and repair
Radiotherapy exerts its therapeutic effect primarily through the cytotoxic DNA damage it induces in proliferating cancer cells. This damage occurs either through direct absorption of radiation energy or indirectly via free radicals produced by IR [9]. DNA damage includes base damage, interstrand crosslinks, SSB, and, most notably, DSB, the latter being the most harmful [10] (Figure 1). In response, tumor cells initiate the DDR and arrest the cell cycle to repair the damaged DNA. Different types of DNA damage activate various repair mechanisms, such as mismatch repair, nucleotide excision repair (NER), non-homologous end joining (NHEJ), and homologous recombination (HR) for DSBs [11]. Simultaneously, DNA damage checkpoints are activated, halting the cell cycle to allow for repair. The efficiency of the DDR is crucial in determining the fate of cancer cells following IR.
During cancer cell evolution, several molecular signaling pathways have emerged to counteract radiation-induced damage, contributing to cancer cell radioresistance and, ultimately, radiotherapy failure [12]. Furthermore, a subset of cancer cells not only becomes more radioresistant but also more aggressive, promoting metastasis [13]. Therefore, understanding the factors that enhance DDR in tumor cells is critical for improving their radiosensitivity.
2.2 Enhanced DDR leads to radioresistance
DNA damage activates a cascade of biochemical reactions in response to IR, triggering various cellular responses. DNA damage sensors detect the damage and recruit DDR core kinases and other regulatory proteins to the damage sites, initiating the repair process [14,15].
2.2.1 DNA damage sensors
Sensors such as H2AX, the MRE11-RAD50-NBS1 (MRN) complex, Ku70/Ku80, MDC1, and 53BP1 recognize DNA damage signals. They recruit DDR core kinases and regulatory elements to the DNA break sites, initiating the repair process (Figure 2) [16,17,18]. Notably, H2AX is rapidly phosphorylated in response to DSBs, forming γH2AX foci, which serve as markers for DSBs and provide insights into the effectiveness of radiotherapy [19]. The MRN complex plays a key role in DSB sensing and signal transduction, initiating repair pathways [20]. Ho et al. identified that elevated expression of the MRN complex has been linked to increased radioresistance and poor outcomes in rectal cancer [21]. Similarly, high expression levels of Ku70/Ku80, MDC1, and 53BP1 are associated with radioresistance across multiple cancers [22,23,24]. Thus, these sensors may serve as reliable markers for predicting clinical radiotherapy outcomes.
DNA-PKcs are mobilized and activated by the Ku-bound DSB termini. The MRN complex facilitates ATM recruitment to DSBs. ATR binds to replication protein A (RPA)-coated ssDNA through ATRIP, initiating various pathways responsible for DNA repair and cell cycle arrest post-radiation.
2.2.2 DDR core kinases
DDR core kinases, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia-telangiectasia mutated (ATM), and ATM and Rad3-related (ATR), initiate the DDR signaling cascade in mammalian cells [17]. DNA-PK, comprising Ku70, Ku80, and DNA-PKcs, is essential for the NHEJ pathway, responding quickly to DSBs. Ku70/80 senses DSBs and initiates NHEJ, followed by the recruitment of DNA-PKcs to the damaged site [25]. DNA-PKcs undergoes self-phosphorylation and phosphorylates downstream targets [17,26]. A suppressor of DNA repair, LRRC31, interacts with Ku70/Ku80 and ATR, inhibiting DNA-PKcs recruitment and enhancing the radiosensitivity of breast cancer brain metastasis to radiation [27]. DNA-PKcs also stabilize SOX2 in glioma stem-like cells (GSCs), promoting resistance by maintaining GSCs in a stem cell state. Inhibiting DNA-PKcs pharmacologically enhances the radiosensitivity of glioblastoma xenografts [28]. Furthermore, recent studies have shown that long non-coding RNAs (lncRNA) LINC00312 [29] and microRNA (miRNA) miR-145 [30,31] hinder DNA-PKcs recruitment to DSB sites, promoting degradation and increasing tumor radiosensitivity.
When DNA damage occurs, ATM and ATR activate DDR repair mechanisms, promoting either cell survival or apoptosis (Figure 2). ATM is vital for maintaining cell cycle checkpoints, repairing IR-induced DSBs, and telomere maintenance [32]. In response to DSBs, the MRN complex recruits ATM, which activates the DDR cascade, including γH2AX signaling and phosphorylation of substrates such as checkpoint kinase 2 (CHK2), leading to cell cycle arrest and allowing time for DNA repair [17]. ATR is activated by single-stranded DNA (ssDNA) and, through ATR-interacting protein (ATRIP), binds to ssDNA at damage sites [33]. ATR then phosphorylates CHK1, causing a cell-cycle arrest at the G2-M phase to facilitate DNA repair [17]. Enhanced activation of ATR-CHK1 and ATM-CHK2 pathways has been reported in cancer stem cells (CSCs) of several solid tumors, contributing to their radioresistance [34,35,36]. Increased ATM or ATR expression in tumors is also associated with radiation resistance [37,38].
Given their key roles in DDR, ATM and ATR kinases are promising targets for improving radiotherapy outcomes. Reported ATM inhibitors include caffeine, wortmannin, CP-466722, KU-55933, KU-60019, and KU-559403, while ATR inhibitors include schisandrin B, NU6027, NVP-BEZ235, VE-821, VE-822, AZ20, and AZD6738 [39,40]. However, concerns about increased toxicity to normal tissues remain, and further examination is required to optimize their selective use alongside radiotherapy.
2.2.3 Other DDR proteins
Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme, is one of the 18 members of the PARP protein family. The PARP family senses DNA gaps, transfers single ADP-ribose or PAR to itself or other proteins, and recruits DNA repair proteins to DNA damage sites, playing a pivotal role in DNA repair [41,42]. Among them, PARP-1, a prominent member, is the most extensively researched nuclear enzyme in relation to DNA repair [43,44]. Specifically, PARP-1 is involved in base excision repair following SSBs [43] and participates in alternative DNA repair processes such as NER, enhancing cancer cell resistance to radiation [45]. While inhibiting PARP-1 compromises its repair capabilities for DNA SSB, this inhibition is not lethal since DNA damage can be rectified through other pathways, predominantly HR [46]. Notably, breast-cancer-associated genes 1 and 2 (BRCA1 and BRCA2) are vital components of HR [47,48]. Mutations in these genes, when combined with PARP-1 inactivation, lead to synthetic lethality and cell death [49,50]. To enhance the radiosensitivity of cancers with BRCA1/2 mutations, such as prostate, breast, and pancreatic cancers, clinicians frequently employ IR alongside PARP inhibitors [51,52,53,54]. A clinical trial focusing on triple-negative breast cancer (TNBC) demonstrated that combining the PARP inhibitor olaparib with radiotherapy at an early stage increased radiotherapy efficacy and exhibited promising safety profiles for high-risk TNBC patients [55].
In addition to DNA damage sensors and kinases, cell cycle checkpoint kinases such as CHK1 and G2 Checkpoint Kinase not only provide time for DNA repair but also contribute to tumor radiotherapy resistance [56,57]. As shown in Figure 2, ssDNA activates ATR, which phosphorylates and activates CHK1. CHK1 then phosphorylates CDC25C and WEE1, leading to the activation of WEE1 and the inactivation of CDC25C. This results in G2 phase arrest, allowing DNA repair [58,59]. CHK1 and WEE1 exhibit heightened expression in several cancer types, notably high-grade serous ovarian carcinoma and breast cancer [60,61]. Due to their roles in DDR, CHK1 and WEE1 have been targeted as anticancer agents. Inhibiting WEE1, CHK1, or both prompts tumor cells to proceed into mitosis without repairing DNA, triggering apoptosis or cell death. This approach has shown promise clinically, especially in ovarian cancer. However, early-stage clinical trials have shown that the first-in-human WEE1 inhibitor, adavosertib, is limited by dose-limiting adverse events [59]. Thus, combining WEE1 inhibitors with radiotherapy may alleviate adverse effects. Additionally, studies have found that post-radiation, tumor cells recruit caspase-activated DNase (CAD) to DNA damage sites, selectively cleaving DNA and inhibiting replication. Inhibition of CAD contributes to radiotherapy sensitivity [62]. Thus, targeting the G2 cycle checkpoint may improve radiotherapy efficacy.
To enhance radiotherapy sensitivity and improve survival rates, researchers are focusing on small molecular inhibitors targeting DNA repair pathways and cell cycle checkpoint kinases. Among emerging therapies, PARP inhibitors have been particularly successful, exploiting synthetic lethality to target tumors. Several PARP inhibitors, such as Talazoparib, Rucaparib, Niraparib, and Olaparib, have been approved by the food and drug administration (FDA) for oncological use [63]. However, resistance to DDR inhibitors remains challenging in clinical settings, leading to increased recurrence and diminished outcomes. Resistance mechanisms include reversion mutations, epigenetic changes, replication fork stabilization, and increased drug efflux [64,65]. Understanding these mechanisms and developing strategies to counter resistance is crucial for optimizing radiotherapy outcomes.
3 Tumor microenvironment (TME) and radiotherapy resistance
In oncology, the understanding of cancer has expanded beyond a cancer cell-centric view to encompass non-malignant cells and other non-cellular components, collectively known as the TME. The TME includes tumor cells, infiltrating immune cells, cancer-associated fibroblasts (CAFs), their secretions, extracellular matrix (ECM) components, and hypoxia [66]. TME studies, including preclinical tumor models, have shown that TME cells and their secretions play a key role in cancer pathogenesis and therapeutic resistance, making them attractive therapeutic targets.
3.1 Hypoxia
3.1.1 Role of tumor hypoxia in therapy resistance
Tumor hypoxia is a common feature of the microenvironment in solid tumors [67,68], primarily resulting from an imbalance between poor vascularization and high oxygen consumption by tumor cells [69]. Hypoxia induces a tumor-adapted phenotype, altering signaling, gene expression, and metabolism [70]. Both hypoxia and hypoxia-induced phenotypic changes contribute to radiotherapy resistance [71], making hypoxia a critical predictor of treatment resistance and poor clinical outcomes [72]. Understanding the factors contributing to hypoxic tumor resistance can guide more effective treatment strategies.
3.1.2 Mechanisms of hypoxia-induced resistance
3.1.2.1 Insufficient oxygen
Much of the tumor damage caused by IR is mediated indirectly via the generation of reactive free radicals [73]. These radicals react with oxygen to form ROS, which aggravates radiation damage to DNA, making it irreparable in oxygen-normal tissues [74]. However, under hypoxic conditions, the reaction is limited due to insufficient oxygen, leading to radiation resistance in hypoxic tumor regions (Figure 1). To enhance radiosensitivity in hypoxic tumors, researchers aim to increase oxygen levels using various methods, including hemoglobin transport, erythropoietin stimulation of hemoglobin production [75], or the use of artificial blood substances like perfluorocarbons to deliver oxygen [76,77]. Suppressing oxygen consumption is another strategy to eliminate tumor hypoxia. FDA-approved drugs like Papaverine and Atovaquone alleviate hypoxia by targeting mitochondrial electron transport chain complexes [78,79,80]. Metformin, initially used for type 2 diabetes, also reduces tumor mitochondrial oxygen consumption. Several ongoing clinical trials are exploring metformin as a tumor oxygenating agent (NCT04275713, NCT03510390, NCT02394652, Phase II).
In addition to insufficient oxygen supply, hypoxia-adapted phenotypic modulations are also reasons for tumor cells’ radiotherapy resistance.
3.1.2.2 Hypoxia-inducible factor-1 (HIF-1)
HIF-1 is a crucial transcription factor that regulates cellular responses to hypoxia. It is a heterodimer comprised of one of three hypoxia-inducible alpha subunits (HIF-1α, HIF-2α, or HIF-3α) and a constitutively expressed subunit, HIF-1β [82]. Among these, HIF-1 is the most significant, formed by HIF-1α and HIF-1β. HIF-1α is expressed in nearly all cells, with its expression tightly regulated by oxygen levels. The biological function of HIF-1 is activated only when HIF-1α binds to HIF-1β. Under hypoxic conditions, HIF-1α is stably expressed and translocates to the nucleus, where it regulates downstream gene expression by binding to hypoxia-responsive elements of target genes. Elevated levels of HIF-1α confer radioresistance through various pro-cancer mechanisms, including cell cycle arrest, altered energy metabolism, autophagy, epithelial-mesenchymal transition (EMT), apoptosis, DDR, and modulation of tumor immunity [81]. Studies indicate that HIF-1α influences cell cycle modulation and promotes nonhomologous end joining during post-radiation DNA repair, reducing apoptotic cell death in cervical carcinoma, oral squamous cell carcinoma, and prostate cancer cells [82,83,84].
The serine peptidase inhibitor Kazal type 1 is secreted in a HIF-dependent manner, reducing radiation-induced DNA damage and enhancing radioresistance in adjacent cancer cells via epidermal growth factor receptor and nuclear factor erythroid 2-related factor 2 [85]. HIF-1α also induces the expression of autophagy-related genes such as beclin and LC3-II, activating autophagy [86,87]. Hypoxia-induced autophagy may diminish radiosensitivity by helping cancer cells adapt to metabolic stress from limited oxygen and nutrient availability [88,89,90], particularly in hepatoma, colon cancer, lung cancer, breast cancer, and glioma [86,87,88,91,92]. However, irradiated hypoxic cancer cells can sometimes undergo autophagic death [88,89,93], suggesting that hypoxia-induced autophagy may have contrasting roles in radiotherapy resistance depending on the context.
Research has shown that HIF-1-deficient tumors exhibit greater sensitivity to radiotherapy compared to their wild-type counterparts [94,95,96]. Given its pivotal role in overcoming radiotherapy resistance due to tumor hypoxia, numerous HIF-1 inhibitors are currently under development [97]. Despite extensive clinical trials conducted to date [98,99,100,101], no specific HIF1 inhibitors have been adopted in general clinical practice [74,102]. Therefore, further research is warranted to improve the radiosensitivity of hypoxic tumors through HIF-1 inhibition.
3.1.2.3 Warburg effect
Hypoxic tumor zones adapt to oxygen and nutrient scarcity by shifting energy metabolism from mitochondrial oxidative phosphorylation to glycolysis, known as the Warburg effect. This metabolic switch forces hypoxic tumor cells to generate ATP anaerobically, resulting in decreased ROS production and intracellular accumulation of reduced glutathione (GSH) [103,104]. Increased GSH levels may enhance the radioresistance of hypoxic tumors by boosting their antioxidant capacity [105]. Additionally, this metabolic reprogramming can lead to acidosis, promoting malignant growth and further enhancing radiotherapy resistance [106,107,108]. Researchers propose designing radiosensitizers that activate in low pH environments to target hypoxic tumors specifically. The metabolic switching in hypoxic tumor cells is primarily driven by HIF-1-mediated expression of critical enzymes and regulators of carbohydrate metabolism, including hexokinase 2, pyruvate dehydrogenase kinase 1, and glucose transporter 1, all integral to the Warburg effect [103,104,109]. Other factors, such as the pentose phosphate pathway [110], tumor necrosis factor receptor-associated protein1 [111,112,113], the cellular energy sensor AMP-activated protein kinase [114], and certain microRNAs and circular RNAs [115], also influence cancer cell energy metabolism in response to hypoxia, affecting the radiotherapeutic outcomes for hypoxic tumors.
3.1.2.4 Heat shock transcription factor 1 (HSF1)
HSF1 is responsible for upregulating inducible heat shock proteins (HSP90, HSP70, and HSP27) and is activated in cancer cells under hypoxic stress [116]. These proteins play a protective role, shielding tumor cells from post-radiation cell death and replicative senescence, thereby contributing to radioresistance [116]. HSF1 is crucial for processes such as G2 cell cycle arrest following radiation, the repair of double-stranded DNA breaks [117], the intrinsic promotion of EMT [118], and the upregulation of multidrug resistance 1 expression, which can extrude small molecule radiosensitizers from hypoxic tumor cells [119]. Targeting the mechanisms mediated by HSF1 and HSPs could enhance the sensitivity of hypoxic tumor cells to radiotherapy.
3.1.2.5 CSCs
CSCs exhibit increased resistance to radiotherapy compared to non-stem cancer cells, allowing them to survive treatment and potentially trigger cancer relapse [120]. Hypoxic tumors facilitate EMT through mechanisms such as tumor acidosis and exosome release from hypoxia-stressed cells, which increases the population of radio-resistant CSC-like phenotypes [121]. Central to this process are HIFs, which activate key survival pathways, including transforming growth factor (TGF)-β, Notch, Hedgehog, Wnt/β-catenin, and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR [122]. These pathways support CSC survival in hypoxic conditions by preserving their phenotype, facilitating self-renewal, and promoting aggressive migration, culminating in heightened radioresistance [123]. Thus, developing radiosensitizing agents targeting hypoxic tumor cells may enhance their sensitivity to radiotherapy and reduce the pool of radioresistant CSCs.
Other cellular mechanisms and regulatory pathways in response to hypoxia in cancer cells include hypoxia-induced endoplasmic reticulum (ER) stress and the expression of glucose-regulated proteins [124,125], epigenetic regulation, and exosome generation. These hypoxia-induced responses contribute to the radioresistance of cancer cells. A deeper understanding of the mechanisms behind hypoxic tumor resistance to radiotherapy has revealed several strategies to enhance radiosensitivity. These include artificial oxygenation to improve oxygen delivery to hypoxic tumors [126,127], the use of hypoxia-activated prodrugs that generate cytotoxic agents or radiosensitizers, and the application of hypoxia positron emission tomography (PET) imaging in radiation therapy [128,129]. While these strategies present promising avenues for targeting hypoxic tumors, a single approach is insufficient. Thus, further exploration of the complex cellular interactions and mechanisms within adaptively hypoxic tumor cells is essential to develop synergistic therapeutic strategies (Figure 3).
Schematic representation of intratumoral hypoxia and the key hypoxia-induced responses driving the radioresistance of hypoxic tumors. These responses include reduced ROS production due to diminished oxygen availability, upregulation of HIF-1 expression and its oncogenic effects on downstream genes, generation of GSC-like cells, reconfiguration of energy metabolism, autophagy, and ER stress.
3.2 CSCs
CSCs are a distinct subset of cells found in tumorous tissues that possess the ability to both renew themselves and give rise to a heterogeneous population of tumor cells [130]. These cells display several characteristics, including enhanced DNA damage repair, efficient ROS scavenging, prolonged dormancy, reduced cell adhesion, and potent immunosuppressive properties. Consequently, CSCs play a pivotal role in tumor metastasis, recurrence, radiotherapy failure, and the overall poor prognosis observed in cancer patients [131,132].
The radioresistance of CSCs is attributed to their enhanced ability to repair DNA damage and regulate ROS levels (Figure 4). When tumor tissues are exposed to IR, CSCs activate critical checkpoint pathways, such as ATR-CHK1 and ATM-CHK2, upregulating genes involved in DNA repair and cell cycle arrest to facilitate damage repair [35,133,134]. The transcription factor c-Myc serves as a master regulator of various cellular programs, significantly contributing to the radioresistance of stem-like populations in nasopharyngeal carcinoma (NPC) by upregulating DNA damage checkpoints CHK1 and CHK2 [135,136]. Oct4, a CSC marker and transcription factor, confers radioresistance to head and neck squamous cell carcinoma cells by regulating the cell cycle checkpoint kinases CHK1 and WEE1 and HR repair genes PSMC3IP and RAD54L. Combining radiotherapy with PARP inhibitors may induce synthetic lethality in Oct4-deregulated tumors [137]. SOX2, another crucial CSC biomarker, is essential for stem cell self-renewal, reprogramming, and homeostasis [138]. It also contributes to radioresistance by inducing cell cycle arrest, enabling cancer cells to evade DNA damage checkpoints [139]. THOC2 and THOC5 enhance the radioresistance of TNBC by increasing stemness through SOX2 [140]. Musashi1, a CSC marker, regulates DNA-PKcs expression, leading to enhanced DNA repair responses and subsequent radioresistance in GSCs [141]. Ubiquitin-Specific Protease 1, highly expressed in GSCs, stabilizes DDR regulators ID1 and CHK1, thereby promoting radioresistance [142].
GSCs exhibit radiotherapy resistance due to enhanced DNA repair capabilities, strong ROS scavenging capacity, and multiple signaling pathways maintaining stemness and inhibiting apoptosis.
Multiple signaling pathways facilitate both stemness and radioresistance in tumor cells. The activation of the JAK2/STAT3 pathway enhances colorectal cancer stemness by upregulating cyclin D2 expression following radiotherapy, minimizing DNA damage accumulation and contributing to radioresistance [143]. The PI3K/AKT/mTOR pathway reduces apoptosis when activated, inducing radioresistance in prostate CSCs [144]. Tribble 2 also activates the mTOR pathway, promoting stemness and radioresistance in esophageal squamous cell carcinoma [145]. The TGF-β and WNT/β-Catenin pathways enhance stemness and increase radioresistance in various tumors, including breast and colon cancers and salivary adenoid cystic carcinoma [146,147,148]. Exosomal miR-19b downregulates FBXW7, activating the WNT/β-Catenin pathway and enhancing both stemness and radioresistance in colorectal cancer CSCs [149]. The Forkhead Box Q1/Sirtuin 1/β-Catenin axis and the Ecotropic Virus Integration Site 1/β-Catenin axis also mediate stemness and radioresistance in colorectal cancer [150,151]. In glioblastoma, the cyclin-like protein Spy1 endows cancer cells with self-renewal capabilities and downregulates CAP-Gly Domain-Containing Linker Protein 3, whose expression promotes glycolytic flux, leading to GSC radioresistance [152]. NRP1, a transmembrane glycoprotein, enhances stemness and potentiates radioresistance in breast cancer cells by reducing radiation-induced apoptosis [153]. Integrin β1 increases stemness in oral squamous carcinoma cells and induces radioresistance by suppressing radiation-induced apoptosis [154].
In addition to their enhanced DNA repair capabilities, CSCs can prevent DNA damage by efficiently clearing ROS. Some CSCs have developed highly effective ROS scavenging systems to maintain low ROS levels, with antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase exhibiting significant activity [155,156,157]. Elevated ROS levels can activate HIF, triggering pro-survival and developmental pathways like Notch, WNT, and Hedgehog, which support CSC survival [158]. Research has also identified a negative feedback loop between ROS and COX-2 in CSCs, where increased ROS induces COX-2 expression, which in turn reduces ROS accumulation, promoting CSC enrichment and metastasis [159]. Autophagy, crucial for maintaining cellular homeostasis, is recognized as a key resistance mechanism in metastatic prostate CSCs, significantly enhancing ROS clearance [160,161]. Consequently, CSCs exhibit heightened sensitivity to fluctuations in the oxidant/antioxidant balance, acquiring resistance under both low and elevated ROS conditions.
Furthermore, CSCs primarily remain in a quiescent state, residing in the highly resistant G0 phase during the cell cycle, which minimizes radiation-induced DNA damage [162]. IR can induce a radioresistant stemness phenotype in glioma stem cells in GBMs by promoting autophagy through the Wnt/β-catenin pathway [163]. Similarly, autophagy protects leukemia stem cells from radiotherapy toxicity, enhancing their survival [164]. Studies indicate that inhibiting autophagy-related proteins, specifically SLC7A5/LAT1 and ATG5, increases radiosensitivity in head and neck squamous cell carcinomas (HNSCC) [165]. Solid tumor CSCs predominantly reside in hypoxic niches [166], which may shield them from radiation damage through reduced ROS production, decreased DNA damage, and the activation of the HIF signaling pathway [167,168]. Additionally, CSCs can emit immunosuppressive signals, modifying their microenvironment into an immunosuppressive milieu that fosters tumor growth and contributes to radioresistance [169].
Recent research underscores the pivotal role of CSCs in tumor radioresistance. By enhancing our understanding of potential therapeutic targets for CSC radiosensitization, we can develop more effective and safer combination strategies to improve cancer patients’ life expectancy and treatment outcomes.
Clarifying the regulatory mechanisms and identifying CSC biomarkers is a primary focus of current research. In preclinical studies, significant efforts have been made to restore radiosensitivity by targeting CSCs. For example, DNA-PK stabilizes SOX2, maintaining GSC stemness. The DNA-PK inhibitor NU7441 effectively reduces stem cell sphere formation and sensitizes tumors to radiotherapy in vivo [28]. Additionally, delivering miR-145, which targets multiple stemness-related transcription factors, reduces stemness and reverses the radioresistance of colorectal CSCs [170]. Combining radiotherapy with glimepiride, a type 2 diabetes treatment, disrupts GSC maintenance and sensitizes tumors to radiation by reducing glycolysis [152]. BEZ235, a dual PI3K/mTOR inhibitor, effectively sensitizes prostate CSCs to radiotherapy by decreasing stemness [144]. Moreover, methyltransferase-like 14 and miR-99a-5p downregulate Tribble 2, while Tribble 2-induced activation of the mTOR pathway can be inhibited by histone deacetylase 2 (HDAC2) inhibitors, restoring radiosensitivity in esophageal squamous CSCs [145]. Despite these preclinical efforts, few clinical trials have investigated the combination of radiotherapy with CSC-targeting therapies. One example is a phase I study (NCT01068327) that evaluated the safety and efficacy of nelfinavir, an Akt inhibitor, combined with SBRT for locally advanced, borderline, or unresectable pancreatic adenocarcinoma. The trial concluded that concurrent SBRT plus nelfinavir was tolerable and safe for patients with locally advanced pancreatic cancer, although the efficacy of this combination requires further investigation [171].
Despite numerous challenges, researchers remain committed to innovative approaches to eradicate CSCs and enhance their responsiveness to radiotherapy. Future studies on CSC characteristics – including novel markers, signaling pathways, and the TME – are anticipated to be a major focus. Although high-quality clinical trials confirming the efficacy of these strategies are currently lacking, ongoing research provides optimism for developing more effective methods to eliminate CSCs and overcome radiotherapy resistance.
3.3 Immune microenvironment
The immune system is the primary defense against cancer and plays a critical role in cancer progression [66]. In recent years, immunotherapy has emerged as a leading strategy in cancer treatment, yet its success is often limited to specific patient subsets, particularly in non-small cell lung cancer (NSCLC). Radiotherapy can enhance the immune response to tumors through multiple mechanisms, including modifying immunosurveillance by altering neoantigen expression, inducing the abscopal effect [172,173], activating the cGAS-STING pathway, and increasing type I interferon transcription, thereby boosting the innate immune response [174]. Consequently, the combination of radiotherapy and immunotherapy is gaining recognition as a promising therapeutic approach. However, it is essential to recognize that radiotherapy can simultaneously promote anti-tumor immune responses and activate immunosuppressive mechanisms, potentially leading to therapy resistance.
When tumor cells cannot repair radiation-induced DNA damage, they enter a state of senescence [175]. In this state, they release immunosuppressive cytokines, such as TGF-β1 and chemokine (C-C motif) ligand 2, which attract myeloid cells with immunosuppressive phenotypes, including myeloid-derived suppressor cells and M2-like tumor-associated macrophages. These cells inhibit CD8+ T cell activation and function, facilitating tumor immune resistance and diminishing radiotherapy efficacy [176,177,178]. The excessive activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway post-radiotherapy is closely associated with tumor radioresistance. Key downstream effectors of AKT, including NF-κB and mTOR, enhance cell survival by strengthening the DDR and regulating autophagy and apoptosis [179,180]. Furthermore, the PI3K-AKT pathway is instrumental in sustaining HIF-1α transcription in tumors [181]. Targeting the PI3K-AKT-mTOR pathway could reduce tumor hypoxia and induce G2/M phase arrest in cells sensitive to radiation-induced DNA damage [182,183].
IR also increases programmed death ligand 1 (PD-L1) expression through various mechanisms, undermining the cytotoxic effects of CD8+ CTLs [184,185]. Combining radiation with anti-PD-L1 therapy may curb immune evasion, enhancing the anti-cancer efficacy of radiotherapy [186]. PD-L1 interacts with programmed death-1 (PD-1), leading to T cell apoptosis, dysfunction, and exhaustion, thereby inhibiting the activation and proliferation of tumor antigen-specific CD8+ T cells, which facilitates tumor immune escape [187]. Pembrolizumab, a PD-1 inhibitor, blocks this interaction [188]. Recently, Pembrolizumab has advanced significantly as an immunotherapy for various tumors, and its combination with radiotherapy as a radiosensitizer is receiving increasing attention [189]. While radiotherapy can eliminate local tumor cells, Pembrolizumab may enhance the abscopal effect by activating systemic immune responses. Clinical studies are currently investigating the combination of Pembrolizumab and radiotherapy for multiple solid tumors, including NSCLC, melanoma, and HNSCC (Table 1) [190,191,192]. Moreover, combining radiotherapy with anti-CTLA-4 and related immunomodulatory agents may yield synergistic benefits [193,194].
Registered ongoing clinical trials of small-molecule chemical radiosensitizers in the past 5 years
| Trial ID | Intervention | Conditions | Phase | Study start |
|---|---|---|---|---|
| NCT04381806 | 5-ALA | Solid tumor | I | 2020-07-30 |
| NCT04634877 | Cisplatin | High-risk endometrial cancer | III | 2021-01-10 |
| NCT05626829 | Tranilast | NPC | II | 2022-07-20 |
| NCT06103617 | Penicillamine | Recurrent head and neck cancer | II | 2023-11-15 |
| NCT03946202 | Hydrogen peroxide | Advanced/recurrent breast cancer | II | 2020-06-16 |
| NCT06142318 | Pirfenidone | HNSCC | II | 2023-11-15 |
| NCT04683679 | Pembrolizumab | Triple-negative or hormone-receptor positive/Her2 negative breast cancer | II | 2021-04-21 |
Recent findings reveal that elevated expression of the tumor-specific E3 ligase TRIM7 correlates with poor outcomes in NPC due to its role in impairing mitochondrial DNA release, disrupting STING/STING-dependent interferon signaling. This disruption compromises CD8+ T cell-mediated anti-tumor immune responses and contributes to radiation therapy resistance [195]. Understanding the interplay between the positive and negative effects of radiotherapy within the tumor immune environment is crucial for developing strategic combinations of radiotherapy and immunotherapy to enhance overall treatment efficacy.
3.4 Cancer‑associated fibroblasts (CAFs)
CAFs are a critical and adaptable cell population in the TME. Through dynamic interactions with tumor cells, they provide structural support and functional assistance, promoting tumor progression and therapy resistance [196]. CAFs induce EMT and enhance the CSC phenotype by releasing paracrine exosomes that activate TGF-β signaling [197,198,199], thereby increasing tumor radiation resistance. CAF-derived exosomes contain elevated levels of miR-935p compared to those from normal fibroblasts, leading to decreased radiation-induced apoptosis in colorectal cancer cells [200]. In esophageal squamous cell carcinoma, chemokine CXCL1 secreted by CAFs confers radioresistance by regulating the DDR in a ROS-dependent manner [201]. Similarly, in NPC, CAFs enhance radioresistance and reduce DNA damage through IL-8 secretion, activating NF-κB signaling [202]. Furthermore, exosomes secreted by CAFs interact with tumor cells via retinoic acid-inducible gene-I (RIG-I), amplifying radioresistance [203]. CAFs also diminish the efficacy of radiotherapy by fostering an immunosuppressive environment enriched with immunosuppressive cells and inhibiting effector immune cells [204,205]. A transcriptomic analysis of CAFs following radiotherapy in an NSCLC model revealed the upregulation of nine distinct MDM2 transcripts. Increased expression of these MDM2 variants correlates with lung radiosensitivity [206], indicating a potential role for CAFs in mediating radioresistance post-therapy. Although CAFs significantly influence the TME and contribute to radioresistance, the nuances of how radiotherapy affects CAFs and their subsequent interactions with the TME remain underexplored. An in-depth study of this interplay is essential, as it holds potential for guiding innovative therapeutic approaches beyond merely inhibiting or eradicating tumor cells.
The complexity of the TME enables cancer cells to develop resistance to radiotherapy through multiple mechanisms. To overcome this resistance, researchers are exploring ways to target these microenvironmental components. Currently, several small molecule drugs are undergoing preclinical studies (Table 1). Tranilast, originally used as an anti-allergic drug, has recently been found to possess anti-tumor properties, particularly when combined with radiotherapy, where it exhibits radiosensitizing effects [207]. Its potential as a radiosensitizer is being actively explored, particularly regarding its role in modulating the TME and combating fibrosis. Tranilast inhibits TGF-β activity, a key factor in the TME that promotes tumor cell proliferation, invasion, and metastasis, and plays a critical role in radioresistance [208]. By blocking the TGF-β signaling pathway, tranilast reduces tumor cell radioresistance. It also inhibits CAF activity, diminishing the supportive environment for tumor cells and enhancing the effectiveness of radiotherapy. Although clinical studies on tranilast as a radiosensitizer are still in early stages, preliminary results are promising. For instance, in locally advanced tumors such as head and neck cancer and NSCLC, early findings suggest that tranilast can improve local tumor radiosensitivity and enhance overall patient survival [202,209].
However, radiotherapy itself can significantly affect the TME by inducing immune cell infiltration, promoting fibrosis, and activating TGF-β signaling. These changes may enhance the short-term efficacy of radiotherapy but could also contribute to long-term tumor recurrence and resistance. To effectively overcome tumor radioresistance, future research must delve deeper into the factors within the TME that contribute to radiotherapy resistance and their interactions. Identifying these factors will be crucial for discovering new targets to enhance the efficacy of radiotherapy.
4 Other factors
4.1 Epigenetic factors
Epigenetics encompasses mechanisms that influence gene expression without altering the DNA sequence. These mechanisms include DNA methylation, histone modifications (such as acetylation and methylation), and the regulation of non-coding RNAs [210] (Figure 5). Numerous studies have demonstrated a strong correlation between epigenetic modifications and the resistance of tumor cells to radiotherapy [211].
IR can affect cellular epigenetics by acting on DNA, leading to increased methylation levels that impact the transcription of genes like p53. IR also influences histone methylation, acetylation, and RNA adenosine methylation levels in tumor cells by acting on specific enzymes. These radiation-induced responses ultimately contribute to radioresistance.
4.1.1 DNA methylation
DNA methylation involves adding a methyl group to the fifth carbon of cytosine within CpG dinucleotides, a process facilitated by DNA methyltransferases (DNMTs). Radiotherapy can induce changes in DNA methylation or demethylation and affect DNMT activity [212]. For example, in a rat breast cancer study, radiation-induced hypermethylation, mediated by the polycomb repressive complex 2 (PRC2), led to cancer cell dedifferentiation and contributed to radiation-induced breast cancer [213]. Hypermethylation of specific gene promoter regions can silence genes and enhance cancer cell resistance to radiation. Silencing DNA methyltransferase 3B (DNMT3B) has been shown to restore p53 and p21 function through demethylation, resulting in cell cycle arrest and apoptosis [214]. IR can increase DNMT3B levels and methylate p53 and p21, promoting radiation resistance in NPC [215].
4.1.2 Histone modification
Histone modifications, including methylation, acetylation, phosphorylation, and ubiquitination, are crucial for regulating gene expression and are closely tied to transcription and DNA repair [216,217,218]. Radiation significantly affects histone modifications in tumor cells [219]. A notable modification is the trimethylation of histone H3 at lysine 27 (H3K27me3), associated with chromatin condensation and impacting DNA DSB repair. In diffuse intrinsic pontine glioma (DIPG), H3K9me3 levels increase after radiotherapy. A strategy combining radiotherapy with a G9a inhibitor aims to reduce H3K9me3 and DSB repair [220]. While radiation eliminates many cancer cells, it can also induce radioresistance and more aggressive epigenetic phenotypes. Upregulation of the chemokine CXCL12, mediated by histone modification in its promoter, may drive the development of a resistant phenotype during treatment [221]. Research has also linked radiation-induced autophagy to histone methylation, identifying H4K20me3 as critical in inducing autophagy post-irradiation. This autophagy acts as a protective mechanism for NSCLC cells, and inhibiting autophagy-associated histone modifications can enhance cell death following radiation. The broad-spectrum methyltransferase inhibitor 3-deazaneplanocin A (DZNep) significantly inhibits H4K20me3, enhancing radiosensitivity [222].
Histone acetylation activates gene transcription by acetylating lysine residues on histone tails. Aberrant histone acetylation has been linked to radiation resistance [201]. One study found that radiation-resistant populations exhibited widespread histone deacetylation and alterations in the activity of HDACs and histone acetyltransferases. Given the variability of HDAC activity among individuals, assessing tumor HDAC activity prior to radiotherapy is crucial. Patients with high HDAC activity may benefit from radiosensitization with HDAC inhibitors (HDACi) [223].
4.1.3 RNA methylation
Post-transcriptional modifications of RNA molecules are prevalent, with over a hundred known modifications, including N6-methyladenine (m6A), 5-methylcytosine, N1-methyladenosine, and M7G, with methylation being the most common. YTH domain containing 2 (YTHDC2) is an m6A-binding protein [224]. In NPC, YTHDC2 is overexpressed in radioresistant cells. Knockout of YTHDC2 enhances the therapeutic effects of radiotherapy both in vitro and in vivo, whereas its overexpression in radiation-sensitive NPC cells has the opposite effect [225]. In hypopharyngeal squamous cell carcinoma, methyltransferase-like 3 mediates m6A methylation and stabilizes the expression of circCUX1, a specific circRNA. Knocking down circCUX1 increases hypopharyngeal cancer cells’ sensitivity to radiotherapy. Furthermore, circCUX1 inhibits caspase-1 expression, reducing the release of inflammatory cytokines and increasing tolerance to radiotherapy [226].
Chromatin structure has also emerged as a potential target in radiation therapy. Chromatin remodeling complexes, such as the SWI/SNF complex, modulate DNA accessibility, affecting gene expression and potentially contributing to radioresistance [202,203,204]. Additionally, non-coding RNAs, particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been significantly associated with radiation resistance [205,206]. The interplay between epigenetic alterations and radioresistance likely varies across cancer types, emphasizing the need to understand these processes for effective radiosensitizing strategies.
The study of epigenetics is crucial in cancer research. Advances have revealed that certain epigenetic modifiers – such as HDAC inhibitors, DNMT inhibitors, EZH2 inhibitors, and BET inhibitors – can act as radiation sensitizers [227]. These agents impair DNA damage repair, disrupt the cell cycle, and increase oxidative stress, thereby enhancing the anti-tumor efficacy of radiotherapy.
4.2 Non-B-DNA
DNA, the genetic material of human cells, typically exists as double-stranded B-DNA, characterized by Watson–Crick base pairing. However, under certain conditions, repetitive DNA motifs can adopt non-B DNA forms, such as self-annealed hairpins, Z-DNA, three-stranded triplexes (H-DNA), or four-stranded guanine quadruplex structures (G4 DNA) [228,229]. Among these, G4 DNA is the most extensively studied non-B DNA structure.
G4 DNA plays a crucial role in carcinogenesis and the malignant phenotypes of cancer cells [230]. Research indicates that G4 DNA can fold into a quadruplex structure that is less sensitive to IR compared to B-DNA [231]. During radiotherapy, the planar G-quadruplex of G4 DNA can shield free radicals induced by IR, protecting genomic regions rich in G4 DNA from radiation-induced breaks. This process can be further regulated by G4 stabilizers, helping the human genome resist radiation-induced damage [232]. In cancer tissues, the proportion of G4 DNA is upregulated, accelerating genomic instability [233]. The presence of G4 DNA is associated not only with cancer development and tumor malignancy but also with the effectiveness of radiotherapy.
Controlling non-B DNA structures may offer a novel strategy for enhancing radiotherapy sensitivity. One extensively studied approach involves developing small-molecule drugs that specifically recognize and stabilize these structures. For instance, G-quadruplex stabilizers, such as TMPyP4, have been investigated for their potential in radiosensitization [234,235]. Another strategy targets proteins that bind to non-B DNA structures; proteins like Topoisomerase and RPA can stabilize these structures, and targeting their functions could indirectly influence non-B DNA formation [236,237]. Despite numerous laboratory studies suggesting that non-B DNA structures can enhance radiotherapy sensitivity, most research remains limited to cell and animal models. The translation of these findings into clinical applications and the development of safe, effective drugs require further exploration and validation.
5 Discussion
Radiotherapy plays a major role in cancer treatment, yet radioresistance poses significant challenges to achieving optimal therapeutic outcomes. This review has examined the various factors and pathways contributing to tumor radioresistance. Mechanisms such as DNA repair and cell cycle dynamics are critical biological factors driving resistance. Moreover, the TME – characterized by hypoxia, immune evasion, and CSCs – complicates treatment efficacy. Molecular mechanisms, including aberrant signaling pathways, epigenetic modifications, and non-B-DNA, also significantly contribute to radioresistance.
To address tumor resistance to radiotherapy, combining it with targeted drugs that inhibit DNA repair, modulate the TME, or disrupt signaling pathways may overcome this challenge. For instance, PARP inhibitors have been shown to enhance radiotherapy effects by blocking DNA repair mechanisms. Additionally, optimizing the dose distribution and timing of radiotherapy can maximize tumor cell destruction while minimizing damage to healthy tissues.
Recent advancements in immunotherapy have demonstrated immense potential, particularly in cancers where traditional therapies are less effective. Consequently, combining immunotherapy with radiotherapy is considered one of the most promising strategies. Radiotherapy can enhance the exposure of tumor antigens, facilitating immune recognition and attack, while immune checkpoint inhibitors can counteract the immunosuppressive effects of the TME. This combined approach offers potential synergistic effects by activating the immune system while simultaneously destroying tumor cells. An in-depth understanding of the interplay between the advantages and disadvantages of radiotherapy within the tumor immune milieu could pave the way for strategic combinations of radiotherapy and immunotherapy, ultimately enhancing the overall efficacy of treatment.
Since radioresistance arises from multiple factors, different tumor types may develop resistance through distinct regulatory pathways. Overcoming this resistance necessitates tailored molecular interventions or combination therapies specific to each tumor subtype. A deeper understanding of the molecular mechanisms underlying radioresistance, along with insights into their interactions with the TME, could improve radiotherapy efficacy in resistant cancers. Furthermore, advancements in genetic marker identification, molecular profiling, enhanced molecular imaging, and functional assays are opening new avenues for predicting treatment responses, driving the field toward more precise and individualized clinical care.
Acknowledgements
The authors are grateful for the reviewer’s valuable comments that improved the manuscript.
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Funding information: This research was funded by Huzhou Natural Science Foundation Project, Grant number 2023YZ05.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and consented to its submission to the journal, reviewed all the results, and approved the final version of the manuscript. L.J.M. drafted the manuscript and prepared the figures. H.Q.Z. critically revised the manuscript. All authors contributed to this manuscript.
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Conflict of interest: Authors state no conflict of interest.
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Data availability statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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- Correlation analysis of AVPR1a and AVPR2 with abnormal water and sodium and potassium metabolism in rats
- Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota
- Myriad factors and pathways influencing tumor radiotherapy resistance
- Exploring the effects of culture conditions on Yapsin (YPS) gene expression in Nakaseomyces glabratus
- Screening of prognostic core genes based on cell–cell interaction in the peripheral blood of patients with sepsis
- Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management
- Ileocecal mucinous carcinoma misdiagnosed as incarcerated hernia: A case report
- Methyltransferase like 13 promotes malignant behaviors of bladder cancer cells through targeting PI3K/ATK signaling pathway
- The debate between electricity and heat, efficacy and safety of irreversible electroporation and radiofrequency ablation in the treatment of liver cancer: A meta-analysis
- ZAG promotes colorectal cancer cell proliferation and epithelial–mesenchymal transition by promoting lipid synthesis
- Baicalein inhibits NLRP3 inflammasome activation and mitigates placental inflammation and oxidative stress in gestational diabetes mellitus
- Impact of SWCNT-conjugated senna leaf extract on breast cancer cells: A potential apoptotic therapeutic strategy
- MFAP5 inhibits the malignant progression of endometrial cancer cells in vitro
- Major ozonated autohemotherapy promoted functional recovery following spinal cord injury in adult rats via the inhibition of oxidative stress and inflammation
- Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons
- Differential expression of phosphoinositide 3-kinase/protein kinase B and Toll-like receptor/nuclear factor kappa B signaling pathways in experimental obesity Wistar rat model
- The therapeutic potential of targeting Oncostatin M and the interleukin-6 family in retinal diseases: A comprehensive review
- BA inhibits LPS-stimulated inflammatory response and apoptosis in human middle ear epithelial cells by regulating the Nf-Kb/Iκbα axis
- Role of circRMRP and circRPL27 in chronic obstructive pulmonary disease
- Investigating the role of hyperexpressed HCN1 in inducing myocardial infarction through activation of the NF-κB signaling pathway
- Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies
- Quantitative immunohistochemistry analysis of breast Ki67 based on artificial intelligence
- Ecology and Environmental Science
- Screening of different growth conditions of Bacillus subtilis isolated from membrane-less microbial fuel cell toward antimicrobial activity profiling
- Degradation of a mixture of 13 polycyclic aromatic hydrocarbons by commercial effective microorganisms
- Evaluation of the impact of two citrus plants on the variation of Panonychus citri (Acari: Tetranychidae) and beneficial phytoseiid mites
- Prediction of present and future distribution areas of Juniperus drupacea Labill and determination of ethnobotany properties in Antalya Province, Türkiye
- Population genetics of Todarodes pacificus (Cephalopoda: Ommastrephidae) in the northwest Pacific Ocean via GBS sequencing
- A comparative analysis of dendrometric, macromorphological, and micromorphological characteristics of Pistacia atlantica subsp. atlantica and Pistacia terebinthus in the middle Atlas region of Morocco
- Macrofungal sporocarp community in the lichen Scots pine forests
- Assessing the proximate compositions of indigenous forage species in Yemen’s pastoral rangelands
- Food Science
- Gut microbiota changes associated with low-carbohydrate diet intervention for obesity
- Reexamination of Aspergillus cristatus phylogeny in dark tea: Characteristics of the mitochondrial genome
- Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach
- Investigating the impact of wet rendering (solventless method) on PUFA-rich oil from catfish (Clarias magur) viscera
- Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017–2020)
- Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression
- Utility of dairy microbiome as a tool for authentication and traceability
- Agriculture
- Enhancing faba bean (Vicia faba L.) productivity through establishing the area-specific fertilizer rate recommendation in southwest Ethiopia
- Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control
- Perspectives of pteridophytes microbiome for bioremediation in agricultural applications
- Fertilizer application parameters for drip-irrigated peanut based on the fertilizer effect function established from a “3414” field trial
- Improving the productivity and profitability of maize (Zea mays L.) using optimum blended inorganic fertilization
- Application of leaf multispectral analyzer in comparison to hyperspectral device to assess the diversity of spectral reflectance indices in wheat genotypes
- Animal Sciences
- Knockdown of ANP32E inhibits colorectal cancer cell growth and glycolysis by regulating the AKT/mTOR pathway
- Development of a detection chip for major pathogenic drug-resistant genes and drug targets in bovine respiratory system diseases
- Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks
- Transcriptome analysis of adipose tissue in grazing cattle: Identifying key regulators of fat metabolism
- Comparison of nutritional value of the wild and cultivated spiny loaches at three growth stages
- Transcriptomic analysis of liver immune response in Chinese spiny frog (Quasipaa spinosa) infected with Proteus mirabilis
- Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis
- Plant Sciences
- Effect of long-term in-row branch covering on soil microorganisms in pear orchards
- Photosynthetic physiological characteristics, growth performance, and element concentrations reveal the calcicole–calcifuge behaviors of three Camellia species
- Transcriptome analysis reveals the mechanism of NaHCO3 promoting tobacco leaf maturation
- Bioinformatics, expression analysis, and functional verification of allene oxide synthase gene HvnAOS1 and HvnAOS2 in qingke
- Water, nitrogen, and phosphorus coupling improves gray jujube fruit quality and yield
- Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots
- Role of Embinin in the reabsorption of nucleus pulposus in lumbar disc herniation: Promotion of nucleus pulposus neovascularization and apoptosis of nucleus pulposus cells
- Revealing the effects of amino acid, organic acid, and phytohormones on the germination of tomato seeds under salinity stress
- Combined effects of nitrogen fertilizer and biochar on the growth, yield, and quality of pepper
- Comprehensive phytochemical and toxicological analysis of Chenopodium ambrosioides (L.) fractions
- Impact of “3414” fertilization on the yield and quality of greenhouse tomatoes
- Exploring the coupling mode of water and fertilizer for improving growth, fruit quality, and yield of the pear in the arid region
- Metagenomic analysis of endophytic bacteria in seed potato (Solanum tuberosum)
- Antibacterial, antifungal, and phytochemical properties of Salsola kali ethanolic extract
- Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells
- Enhanced osmotic dehydration of watermelon rind using honey–sucrose solutions: A study on pre-treatment efficacy and mass transfer kinetics
- Effects of exogenous 2,4-epibrassinolide on photosynthetic traits of 53 cowpea varieties under NaCl stress
- Comparative transcriptome analysis of maize (Zea mays L.) seedlings in response to copper stress
- An optimization method for measuring the stomata in cassava (Manihot esculenta Crantz) under multiple abiotic stresses
- Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway
- Antioxidant and antimicrobial activities of Salsola imbricata methanolic extract and its phytochemical characterization
- Bioengineering and Biotechnology
- Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration
- New advances in protein engineering for industrial applications: Key takeaways
- An overview of the production and use of Bacillus thuringiensis toxin
- Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma
- Bioelectrochemical biosensors for water quality assessment and wastewater monitoring
- PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection
- Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
- Erratum
- Erratum to “Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM”
- Erratum to “Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation”
- Retraction
- Retraction to “MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB”
- Retraction to “A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis”
- Special Issue on Advances in Neurodegenerative Disease Research and Treatment
- Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson’s disease
- Special Issue on Multi-omics
- Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma
- Gastroesophageal varices in primary biliary cholangitis with anti-centromere antibody positivity: Early onset?
Articles in the same Issue
- Biomedical Sciences
- Constitutive and evoked release of ATP in adult mouse olfactory epithelium
- LARP1 knockdown inhibits cultured gastric carcinoma cell cycle progression and metastatic behavior
- PEGylated porcine–human recombinant uricase: A novel fusion protein with improved efficacy and safety for the treatment of hyperuricemia and renal complications
- Research progress on ocular complications caused by type 2 diabetes mellitus and the function of tears and blepharons
- The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor–CaMKII pathway
- Brucella infection combined with Nocardia infection: A case report and literature review
- Detection of serum interleukin-18 level and neutrophil/lymphocyte ratio in patients with antineutrophil cytoplasmic antibody-associated vasculitis and its clinical significance
- Ang-1, Ang-2, and Tie2 are diagnostic biomarkers for Henoch-Schönlein purpura and pediatric-onset systemic lupus erythematous
- PTTG1 induces pancreatic cancer cell proliferation and promotes aerobic glycolysis by regulating c-myc
- Role of serum B-cell-activating factor and interleukin-17 as biomarkers in the classification of interstitial pneumonia with autoimmune features
- Effectiveness and safety of a mumps containing vaccine in preventing laboratory-confirmed mumps cases from 2002 to 2017: A meta-analysis
- Low levels of sex hormone-binding globulin predict an increased breast cancer risk and its underlying molecular mechanisms
- A case of Trousseau syndrome: Screening, detection and complication
- Application of the integrated airway humidification device enhances the humidification effect of the rabbit tracheotomy model
- Preparation of Cu2+/TA/HAP composite coating with anti-bacterial and osteogenic potential on 3D-printed porous Ti alloy scaffolds for orthopedic applications
- Aquaporin-8 promotes human dermal fibroblasts to counteract hydrogen peroxide-induced oxidative damage: A novel target for management of skin aging
- Current research and evidence gaps on placental development in iron deficiency anemia
- Single-nucleotide polymorphism rs2910829 in PDE4D is related to stroke susceptibility in Chinese populations: The results of a meta-analysis
- Pheochromocytoma-induced myocardial infarction: A case report
- Kaempferol regulates apoptosis and migration of neural stem cells to attenuate cerebral infarction by O‐GlcNAcylation of β-catenin
- Sirtuin 5 regulates acute myeloid leukemia cell viability and apoptosis by succinylation modification of glycine decarboxylase
- Apigenin 7-glucoside impedes hypoxia-induced malignant phenotypes of cervical cancer cells in a p16-dependent manner
- KAT2A changes the function of endometrial stromal cells via regulating the succinylation of ENO1
- Current state of research on copper complexes in the treatment of breast cancer
- Exploring antioxidant strategies in the pathogenesis of ALS
- Helicobacter pylori causes gastric dysbacteriosis in chronic gastritis patients
- IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury
- The predictive value of serum NLR, SII, and OPNI for lymph node metastasis in breast cancer patients with internal mammary lymph nodes after thoracoscopic surgery
- Carrying SNP rs17506395 (T > G) in TP63 gene and CCR5Δ32 mutation associated with the occurrence of breast cancer in Burkina Faso
- P2X7 receptor: A receptor closely linked with sepsis-associated encephalopathy
- Probiotics for inflammatory bowel disease: Is there sufficient evidence?
- Identification of KDM4C as a gene conferring drug resistance in multiple myeloma
- Microbial perspective on the skin–gut axis and atopic dermatitis
- Thymosin α1 combined with XELOX improves immune function and reduces serum tumor markers in colorectal cancer patients after radical surgery
- Highly specific vaginal microbiome signature for gynecological cancers
- Sample size estimation for AQP4-IgG seropositive optic neuritis: Retinal damage detection by optical coherence tomography
- The effects of SDF-1 combined application with VEGF on femoral distraction osteogenesis in rats
- Fabrication and characterization of gold nanoparticles using alginate: In vitro and in vivo assessment of its administration effects with swimming exercise on diabetic rats
- Mitigating digestive disorders: Action mechanisms of Mediterranean herbal active compounds
- Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China
- VSP-2 attenuates secretion of inflammatory cytokines induced by LPS in BV2 cells by mediating the PPARγ/NF-κB signaling pathway
- Factors influencing spontaneous hypothermia after emergency trauma and the construction of a predictive model
- Long-term administration of morphine specifically alters the level of protein expression in different brain regions and affects the redox state
- Application of metagenomic next-generation sequencing technology in the etiological diagnosis of peritoneal dialysis-associated peritonitis
- Clinical diagnosis, prevention, and treatment of neurodyspepsia syndrome using intelligent medicine
- Case report: Successful bronchoscopic interventional treatment of endobronchial leiomyomas
- Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family
- Cystic adenomyoma of the uterus: Case report and literature review
- Mesoporous silica nanoparticles as a drug delivery mechanism
- Dynamic changes in autophagy activity in different degrees of pulmonary fibrosis in mice
- Vitamin D deficiency and inflammatory markers in type 2 diabetes: Big data insights
- Lactate-induced IGF1R protein lactylation promotes proliferation and metabolic reprogramming of lung cancer cells
- Meta-analysis on the efficacy of allogeneic hematopoietic stem cell transplantation to treat malignant lymphoma
- Mitochondrial DNA drives neuroinflammation through the cGAS-IFN signaling pathway in the spinal cord of neuropathic pain mice
- Application value of artificial intelligence algorithm-based magnetic resonance multi-sequence imaging in staging diagnosis of cervical cancer
- Embedded monitoring system and teaching of artificial intelligence online drug component recognition
- Investigation into the association of FNDC1 and ADAMTS12 gene expression with plumage coloration in Muscovy ducks
- Yak meat content in feed and its impact on the growth of rats
- A rare case of Richter transformation with breast involvement: A case report and literature review
- First report of Nocardia wallacei infection in an immunocompetent patient in Zhejiang province
- Rhodococcus equi and Brucella pulmonary mass in immunocompetent: A case report and literature review
- Downregulation of RIP3 ameliorates the left ventricular mechanics and function after myocardial infarction via modulating NF-κB/NLRP3 pathway
- Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease
- The role of Phafin proteins in cell signaling pathways and diseases
- Ten-year anemia as initial manifestation of Castleman disease in the abdominal cavity: A case report
- Coexistence of hereditary spherocytosis with SPTB P.Trp1150 gene variant and Gilbert syndrome: A case report and literature review
- Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells
- Exploratory evaluation supported by experimental and modeling approaches of Inula viscosa root extract as a potent corrosion inhibitor for mild steel in a 1 M HCl solution
- Imaging manifestations of ductal adenoma of the breast: A case report
- Gut microbiota and sleep: Interaction mechanisms and therapeutic prospects
- Isomangiferin promotes the migration and osteogenic differentiation of rat bone marrow mesenchymal stem cells
- Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer
- Circular RNAs as potential biomarkers for male severe sepsis
- Knockdown of Stanniocalcin-1 inhibits growth and glycolysis in oral squamous cell carcinoma cells
- The expression and biological role of complement C1s in esophageal squamous cell carcinoma
- A novel GNAS mutation in pseudohypoparathyroidism type 1a with articular flexion deformity: A case report
- Predictive value of serum magnesium levels for prognosis in patients with non-small cell lung cancer undergoing EGFR-TKI therapy
- HSPB1 alleviates acute-on-chronic liver failure via the P53/Bax pathway
- IgG4-related disease complicated by PLA2R-associated membranous nephropathy: A case report
- Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma
- Metformin mitigates osteoarthritis progression by modulating the PI3K/AKT/mTOR signaling pathway and enhancing chondrocyte autophagy
- Evaluation of the activity of antimicrobial peptides against bacterial vaginosis
- Atypical presentation of γ/δ mycosis fungoides with an unusual phenotype and SOCS1 mutation
- Analysis of the microecological mechanism of diabetic kidney disease based on the theory of “gut–kidney axis”: A systematic review
- Omega-3 fatty acids prevent gestational diabetes mellitus via modulation of lipid metabolism
- Refractory hypertension complicated with Turner syndrome: A case report
- Interaction of ncRNAs and the PI3K/AKT/mTOR pathway: Implications for osteosarcoma
- Association of low attenuation area scores with pulmonary function and clinical prognosis in patients with chronic obstructive pulmonary disease
- Long non-coding RNAs in bone formation: Key regulators and therapeutic prospects
- The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein
- Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential diagnostic markers for rebleeding in patients with esophagogastric variceal bleeding
- G protein-coupled receptor 1 participating in the mechanism of mediating gestational diabetes mellitus by phosphorylating the AKT pathway
- LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1
- The analgesic effect of paeoniflorin: A focused review
- Chemical composition’s effect on Solanum nigrum Linn.’s antioxidant capacity and erythrocyte protection: Bioactive components and molecular docking analysis
- Knockdown of HCK promotes HREC cell viability and inner blood–retinal barrier integrity by regulating the AMPK signaling pathway
- The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes
- Laryngeal non-Hodgkin lymphoma: Report of four cases and review of the literature
- Clinical value of macrogenome next-generation sequencing on infections
- Overview of dendritic cells and related pathways in autoimmune uveitis
- TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway
- Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age
- Profile and antimicrobial susceptibility patterns of bacteria isolated from effluents of Kolladiba and Debark hospitals
- The expression and clinical significance of syncytin-1 in serum exosomes of hepatocellular carcinoma patients
- A histomorphometric study to evaluate the therapeutic effects of biosynthesized silver nanoparticles on the kidneys infected with Plasmodium chabaudi
- PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer
- Analysis of MDA, SOD, TAOC, MNCV, SNCV, and TSS scores in patients with diabetes peripheral neuropathy
- SLIT3 deficiency promotes non-small cell lung cancer progression by modulating UBE2C/WNT signaling
- The relationship between TMCO1 and CALR in the pathological characteristics of prostate cancer and its effect on the metastasis of prostate cancer cells
- Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma
- PHB2 alleviates retinal pigment epithelium cell fibrosis by suppressing the AGE–RAGE pathway
- Anti-γ-aminobutyric acid-B receptor autoimmune encephalitis with syncope as the initial symptom: Case report and literature review
- Comparative analysis of chloroplast genome of Lonicera japonica cv. Damaohua
- Human umbilical cord mesenchymal stem cells regulate glutathione metabolism depending on the ERK–Nrf2–HO-1 signal pathway to repair phosphoramide mustard-induced ovarian cancer cells
- Electroacupuncture on GB acupoints improves osteoporosis via the estradiol–PI3K–Akt signaling pathway
- Renalase protects against podocyte injury by inhibiting oxidative stress and apoptosis in diabetic nephropathy
- Review: Dicranostigma leptopodum: A peculiar plant of Papaveraceae
- Combination effect of flavonoids attenuates lung cancer cell proliferation by inhibiting the STAT3 and FAK signaling pathway
- Renal microangiopathy and immune complex glomerulonephritis induced by anti-tumour agents: A case report
- Correlation analysis of AVPR1a and AVPR2 with abnormal water and sodium and potassium metabolism in rats
- Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota
- Myriad factors and pathways influencing tumor radiotherapy resistance
- Exploring the effects of culture conditions on Yapsin (YPS) gene expression in Nakaseomyces glabratus
- Screening of prognostic core genes based on cell–cell interaction in the peripheral blood of patients with sepsis
- Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management
- Ileocecal mucinous carcinoma misdiagnosed as incarcerated hernia: A case report
- Methyltransferase like 13 promotes malignant behaviors of bladder cancer cells through targeting PI3K/ATK signaling pathway
- The debate between electricity and heat, efficacy and safety of irreversible electroporation and radiofrequency ablation in the treatment of liver cancer: A meta-analysis
- ZAG promotes colorectal cancer cell proliferation and epithelial–mesenchymal transition by promoting lipid synthesis
- Baicalein inhibits NLRP3 inflammasome activation and mitigates placental inflammation and oxidative stress in gestational diabetes mellitus
- Impact of SWCNT-conjugated senna leaf extract on breast cancer cells: A potential apoptotic therapeutic strategy
- MFAP5 inhibits the malignant progression of endometrial cancer cells in vitro
- Major ozonated autohemotherapy promoted functional recovery following spinal cord injury in adult rats via the inhibition of oxidative stress and inflammation
- Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons
- Differential expression of phosphoinositide 3-kinase/protein kinase B and Toll-like receptor/nuclear factor kappa B signaling pathways in experimental obesity Wistar rat model
- The therapeutic potential of targeting Oncostatin M and the interleukin-6 family in retinal diseases: A comprehensive review
- BA inhibits LPS-stimulated inflammatory response and apoptosis in human middle ear epithelial cells by regulating the Nf-Kb/Iκbα axis
- Role of circRMRP and circRPL27 in chronic obstructive pulmonary disease
- Investigating the role of hyperexpressed HCN1 in inducing myocardial infarction through activation of the NF-κB signaling pathway
- Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies
- Quantitative immunohistochemistry analysis of breast Ki67 based on artificial intelligence
- Ecology and Environmental Science
- Screening of different growth conditions of Bacillus subtilis isolated from membrane-less microbial fuel cell toward antimicrobial activity profiling
- Degradation of a mixture of 13 polycyclic aromatic hydrocarbons by commercial effective microorganisms
- Evaluation of the impact of two citrus plants on the variation of Panonychus citri (Acari: Tetranychidae) and beneficial phytoseiid mites
- Prediction of present and future distribution areas of Juniperus drupacea Labill and determination of ethnobotany properties in Antalya Province, Türkiye
- Population genetics of Todarodes pacificus (Cephalopoda: Ommastrephidae) in the northwest Pacific Ocean via GBS sequencing
- A comparative analysis of dendrometric, macromorphological, and micromorphological characteristics of Pistacia atlantica subsp. atlantica and Pistacia terebinthus in the middle Atlas region of Morocco
- Macrofungal sporocarp community in the lichen Scots pine forests
- Assessing the proximate compositions of indigenous forage species in Yemen’s pastoral rangelands
- Food Science
- Gut microbiota changes associated with low-carbohydrate diet intervention for obesity
- Reexamination of Aspergillus cristatus phylogeny in dark tea: Characteristics of the mitochondrial genome
- Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach
- Investigating the impact of wet rendering (solventless method) on PUFA-rich oil from catfish (Clarias magur) viscera
- Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017–2020)
- Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression
- Utility of dairy microbiome as a tool for authentication and traceability
- Agriculture
- Enhancing faba bean (Vicia faba L.) productivity through establishing the area-specific fertilizer rate recommendation in southwest Ethiopia
- Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control
- Perspectives of pteridophytes microbiome for bioremediation in agricultural applications
- Fertilizer application parameters for drip-irrigated peanut based on the fertilizer effect function established from a “3414” field trial
- Improving the productivity and profitability of maize (Zea mays L.) using optimum blended inorganic fertilization
- Application of leaf multispectral analyzer in comparison to hyperspectral device to assess the diversity of spectral reflectance indices in wheat genotypes
- Animal Sciences
- Knockdown of ANP32E inhibits colorectal cancer cell growth and glycolysis by regulating the AKT/mTOR pathway
- Development of a detection chip for major pathogenic drug-resistant genes and drug targets in bovine respiratory system diseases
- Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks
- Transcriptome analysis of adipose tissue in grazing cattle: Identifying key regulators of fat metabolism
- Comparison of nutritional value of the wild and cultivated spiny loaches at three growth stages
- Transcriptomic analysis of liver immune response in Chinese spiny frog (Quasipaa spinosa) infected with Proteus mirabilis
- Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis
- Plant Sciences
- Effect of long-term in-row branch covering on soil microorganisms in pear orchards
- Photosynthetic physiological characteristics, growth performance, and element concentrations reveal the calcicole–calcifuge behaviors of three Camellia species
- Transcriptome analysis reveals the mechanism of NaHCO3 promoting tobacco leaf maturation
- Bioinformatics, expression analysis, and functional verification of allene oxide synthase gene HvnAOS1 and HvnAOS2 in qingke
- Water, nitrogen, and phosphorus coupling improves gray jujube fruit quality and yield
- Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots
- Role of Embinin in the reabsorption of nucleus pulposus in lumbar disc herniation: Promotion of nucleus pulposus neovascularization and apoptosis of nucleus pulposus cells
- Revealing the effects of amino acid, organic acid, and phytohormones on the germination of tomato seeds under salinity stress
- Combined effects of nitrogen fertilizer and biochar on the growth, yield, and quality of pepper
- Comprehensive phytochemical and toxicological analysis of Chenopodium ambrosioides (L.) fractions
- Impact of “3414” fertilization on the yield and quality of greenhouse tomatoes
- Exploring the coupling mode of water and fertilizer for improving growth, fruit quality, and yield of the pear in the arid region
- Metagenomic analysis of endophytic bacteria in seed potato (Solanum tuberosum)
- Antibacterial, antifungal, and phytochemical properties of Salsola kali ethanolic extract
- Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells
- Enhanced osmotic dehydration of watermelon rind using honey–sucrose solutions: A study on pre-treatment efficacy and mass transfer kinetics
- Effects of exogenous 2,4-epibrassinolide on photosynthetic traits of 53 cowpea varieties under NaCl stress
- Comparative transcriptome analysis of maize (Zea mays L.) seedlings in response to copper stress
- An optimization method for measuring the stomata in cassava (Manihot esculenta Crantz) under multiple abiotic stresses
- Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway
- Antioxidant and antimicrobial activities of Salsola imbricata methanolic extract and its phytochemical characterization
- Bioengineering and Biotechnology
- Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration
- New advances in protein engineering for industrial applications: Key takeaways
- An overview of the production and use of Bacillus thuringiensis toxin
- Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma
- Bioelectrochemical biosensors for water quality assessment and wastewater monitoring
- PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection
- Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
- Erratum
- Erratum to “Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM”
- Erratum to “Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation”
- Retraction
- Retraction to “MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB”
- Retraction to “A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis”
- Special Issue on Advances in Neurodegenerative Disease Research and Treatment
- Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson’s disease
- Special Issue on Multi-omics
- Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma
- Gastroesophageal varices in primary biliary cholangitis with anti-centromere antibody positivity: Early onset?
