Home Medicine Causal association between ceramide levels and central precocious puberty: a mendelian randomization study
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Causal association between ceramide levels and central precocious puberty: a mendelian randomization study

  • Doudou Guo ORCID logo , Yating Li ORCID logo , Xin Ning ORCID logo , Yanfen Zhou ORCID logo , Cencen Wang ORCID logo and Xin Li ORCID logo EMAIL logo
Published/Copyright: December 17, 2025
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Open Medicine
From the journal Open Medicine Volume 20 Issue 1

Abstract

Objectives

Ceramides have been implicated in metabolic disorders, but their role in central precocious puberty (CPP) is unclear. This study aimed to assess the causal relationship between ceramide species and CPP using Mendelian randomization (MR).

Methods

Genome-wide association study (GWAS) data were used to construct a ceramide database. MR analyses, including inverse variance weighting (IVW) and Wald Ratio methods, were performed to evaluate causal associations. Sensitivity analyses tested robustness. Gene Ontology (GO) and KEGG enrichment analyses were conducted to explore biological pathways and regulatory genes.

Results

The MR predicted that 17 ceramide species were associated with CPP. Cer(d17:1/20:0), Cer(d17:1/22:0), Cer(d17:1/24:0), and Cer(d18:1/14:0, d16:1/16:0) were linked to increased CPP risk, while total ceramide levels and 12 other subtypes showed protective associations. Enrichment analyses indicated involvement of sphingolipid metabolism and related signaling pathways, with SPTLC1, SPTLC3, and CERS4 framed as plausible pathways.

Conclusions

Our analysis suggests a potential causal relationship between specific ceramide species and CPP. We need more experimental research on specific pathological and physiological mechanisms in the future.

Keywords: ceramide; central precocious puberty; mendelian randomization; blood metabolites; sphingolipid

Introduction

Sphingolipids, found in all mammalian cells, are unique lipids containing amino alcohols in their structure. This family includes ceramide (Cer), monohexosyl ceramide, sphingomyelin, and sphingosine [1]. Ceramide has been identified as a key lipotoxic molecule implicated in the pathogenesis of various metabolic disorders [2], [3], [4]. Elevated ceramide levels, for instance, impair insulin signaling and promote lipid buildup, leading to insulin resistance and atherosclerosis [5], 6]. Notably, animal studies reveal that early-onset obesity raises hypothalamic ceramide levels, advancing puberty via ovarian sympathetic circuits, a process reversible by inhibiting ceramide synthase SPTLC1. It suggests that targeting the ceramide pathway may provide a treatment strategy for precocious puberty [7]. Another observational clinical study using non-targeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for lipid analysis also identified Cer(18:0/15:0), Cer(18:1/16:0), and Cer(18:1/26:0) as potential biomarkers for distinguishing central precocious puberty (CPP) in girls (AUC=0.964) [8]. However, the results of such observational studies are susceptible to unmeasured confounding factors and may not truly reflect the relationship between ceramides and CPP.

Central precocious puberty is a common pediatric endocrine disorder characterized by the early activation of the hypothalamic-pituitary-gonadal axis (HPGA), leading to secondary sexual development before age eight in girls and before age nine in boys. CPP not only promotes the rapid progress of sexual development and affects adult height and mental and behavioral health, but is also accompanied by an increased risk of diseases such as obesity in adulthood, type 2 diabetes, cardiovascular disease, and breast cancer [9]. With a global trend toward earlier puberty, CPP incidence has notably increased in many countries [10], 11]. Understanding the pathogenesis of CPP is thus vital to public health efforts. While risk factors, such as mutations in the MKRN3 gene, obesity, and exposure to endocrine disruptors, have been linked to CPP, its underlying mechanisms and biomarkers remain largely unexplored [12], [13], [14]. In particular, research on ceramide metabolism in CPP is still sparse. Current clinical reports linking ceramide and precocious puberty in children are based on cross-sectional data, which cannot confirm causal relationships [8]. The recent advancements in metabolomics technology have yielded innovative and efficient analytical methods that facilitate the investigation of intricate biological processes associated with metabolic alterations underlying various diseases [15].

Understanding the regulation of ceramides in sphingolipid metabolism is essential for uncovering the mechanisms of CPP and developing early diagnostic and preventive strategies. Research has shown that ceramides, lipid metabolites that accumulate with aging and overnutrition, play a crucial role in obesity-related dysfunction of thermogenic fat cells [16]. Specifically, C16:0 and C18:0 ceramides act as key lipotoxic agents in adipose tissue, skeletal muscle, and liver, disrupting insulin sensitivity, beta-cell function, vascular reactivity, and mitochondrial metabolism [3]. Inhibiting ceramide biosynthesis or promoting its breakdown in rodent models has demonstrated improvements in various metabolic diseases, including diabetes, cardiomyopathy, insulin resistance, atherosclerosis, and fatty liver disease [17]. Early studies have used metabolomic methods to explore the relationship between specific metabolites and disease. Combined with the close relationship between nutrition and energy metabolism and adolescent development, ceramide has a potential association with CPP, but the causal relationship between the two is still unclear [8]. Traditional randomized controlled trials (RCTs) rely on statistical models to quantify relationships between measured variables. However, for studies involving complex, multi-omics data, RCTs face practical constraints. Mendelian Randomization (MR) studies offer a robust alternative by using genetic variants, single nucleotide polymorphisms (SNPs), to proxy for exposures, allowing causal inferences between exposure and outcome [18]. This technique leverages the random assortment of alleles at conception to mitigate confounding factors and reduce the risk of reverse causality [19]. The high heritability of ceramide further supports the utility of MR in these analyses [20].

Given the sparse research on the relationship between ceramide in the blood and CPP, further investigation is essential. This study establishes a novel blood ceramide database using genome-wide association study (GWAS) data for MR analysis, aiming to clarify the causal link between blood ceramide levels and CPP. This approach provides novel insights and potential strategies for CPP.

Materials and methods

Study design and MR assumptions

The process of this study was conducted strictly in accordance with the statement (STROBE-MR), which used Mendelian randomization to enhance observational epidemiological findings [21]. Three key assumptions must be met in MR studies (Figure 1A): (i) the genetic variants (instruments) used must be strongly associated with the exposure; (ii) these variants should be independent of any confounding factors affecting the exposure-outcome relationship; and (iii) the genetic variants should influence the outcome solely through the exposure. The flow chart (Figure 1B) illustrates the overall study design. All methods were performed in accordance with the relevant guidelines and regulations.

Figure 1: Flowchart of the study. (A) Diagram of the MR assumptions of ceramide and central precocious puberty association. (B) Flowchart of the MR study.
Figure 1:

Flowchart of the study. (A) Diagram of the MR assumptions of ceramide and central precocious puberty association. (B) Flowchart of the MR study.

Data source

The four parts of the blood ceramide database established in this study were all from the IEU OpenGWAS project database ( https://gwas.mrcieu.ac.uk/ ), derived from Cadby [22]、McGurk [23]、Chen [24]、Ottensmann [20], et al., and integrated lipidomics and genomics analysis. Each study obtained ethics committee approval and participant informed consent. The first part included 4,492 participants of European ancestry, analyzed approximately 13.68 million SNPs, including 88 ceramide classes, and was validated by 1,565 individuals of European ancestry. The second part included lipidomic GWAS association results for 999 participants of European ancestry, including 12 ceramide classes, seven of which overlapped with the first part. Considering the timing and number of data updates, the final results of this part of the data were based on the metabolites selected in the first part. The third part included 8,096 participants of European ancestry and analyzed approximately 15.4 million SNPs, including four ceramide classes. The last part included 7,147 participants of European ancestry and analyzed approximately 1.28 million SNPs, including four ceramide classes. For the outcome, CPP data were sourced from the FinnGen Consortium (R11), encompassing 202 cases and 434,894 controls of European ancestry (https://www.finngen.fi/en/). Table 1 presents summary information on the data sources for exposure and outcomes, while detailed information for each ceramide is presented in Supplementary Table S1. There is no overlap between exposure and outcome samples.

Table 1:

Detailed information of GWAS summary statistics data.

Trait Population Sample size, n Journal/Consortium PubMed ID First author Pub.date
Ceramide European 4,492 Nat commun 35,668,104 Cadby G 2022-6-6
European 999 Hum mol genet 33,437,986 McGurk KA 2021-1-12
European 8,091 Nat genet 36,635,386 Chen Y 2023-1-12
European 7,174 Nat commun 37,907,536 Ottensmann L 2023-10-31
Central precocious puberty European 435, 096 The FinnGen consortium (R11) – – 2024-6-24

Instrument selection

To ensure the accuracy and validity of MR assessment, Stringent criteria were implemented for the selection of SNPs as instrumental variables (IV): (i) SNPs were required to have genome-wide significance (p<5 × 10−8) for association with ceramide levels. (ii) Only unique, independent SNPs were selected, minimizing linkage disequilibrium (LD) bias with thresholds of r2<0.001 and a clumping distance of 10,000 kb. (iii) minor allele frequency (MAF) > 0.01. (iv) SNPs that may be associated with confounding factors were excluded using the LDtrait online tool (obesity: rs72999033, rs150268548, rs8100204). (v) The assessment using F-statistics (F=R2 × (n – 2)/(1 - R2)) aims to identify and eliminate weak instrumental variables, setting a minimum F statistical threshold of 10 for SNP inclusion [25]. (vi) Harmonization is performed to align alleles of SNPs associated with exposure and outcome, explicitly discarding palindromic SNPs with intermediate allele frequencies or incompatible alleles.

MR analysis and statistical analysis

In the absence of IV pleiotropy, the inverse variance-weighted method (IVW) is considered to be the most reliable MR estimation technique [26]. In our study, we used IVW (IV≥2) and wald ratio (IV=1) with random effects as the primary methods for MR analysis, adjusting the significance threshold to p<0.05 to initially explore the association between ceramide and CPP. In addition, MR-Egger [27] and weighted median (WM) [28] were used as complementary methods to verify the robustness of the results. MR-Egger regression provided estimates of MR adjusted for horizontal pleiotropy [27]. When more than half of the information came from valid instrumental variables, the WM method generated estimates consistent with actual effects [28]. The IVW method served as the main criterion for causal inference, contingent on consistent results across the three approaches.

Sensitivity analyses were performed to evaluate pleiotropy, heterogeneity, and robustness. First, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) [29] and MR-Egger intercept tests [27] assessed horizontal pleiotropy, with p<0.05 indicating its presence. Second, Cochrane Q tests evaluated heterogeneity between IVW and MR-Egger estimates (p<0.05 indicating heterogeneity) [30]. Leave-one-out (LOO) analysis is employed to identify pleiotropic outlier SNPs that significantly impact the causal effect. Finally, funnel plots were also used to assess SNP heterogeneity visually.

All statistical tests were performed with two-tailed analysis, and a p-value of less than 0.05 in each test indicated a significant causal relationship. 99 statistical tests were conducted, and the p-values for each ceramide type were adjusted for multiple comparisons to control for the false discovery rate (FDR). The corrected p-value, denoted as p_adj, was calculated using the Benjamini-Hochberg method, with a significance threshold set at 0.05 divided by 99 (5.56 × 10−3). A p-value < 0.05, but above the Bonferroni-corrected threshold, was considered as suggestive evidence for a potential causal association. Analyses were conducted using R version 4.4.1.

Statistical power analysis

We computed the power in our main MR analyses for each exposure using the online sample size and power calculator for Mendelian randomization with a binary outcome (https://sb452.shinyapps.io/power) based on the sample size of the outcome and an alpha level of 0.05.

Metabolic pathway analysis

To determine the potential functional impact of association variants identified in the MR analysis, we used the Variant Effect Predictor (VEP) annotation tool ( https://asia.ensembl.org/Tools/VEP ) to obtain the genes corresponding to the SNPs used in the forward MR analysis. Gene enrichment analyses were performed using the “clusterProfiler” R package to identify biological functions and pathways, including KEGG and GO, with a significance level of p<0.05.

Ethics statement

Since every piece of data used in this study was taken from publically accessible databases, no further ethical approval was needed. Each group that makes data available to the public got participants’ informed consent and the go-ahead from the appropriate ethical committees before conducting their research.

Results

After screening for instrumental variables, we selected 99 classes from the established pool of ceramides in blood for MR analysis. All SNPs demonstrated F-statistics exceeding 10, indicating strong instrumental variables.

The causal impact of ceramide levels on CPP

Through MR analysis using the IVW and Wald ratio methods, we identified significant associations between CPP and levels of 16 ceramide classes and the total ceramide, as shown in Figure 2. The information corresponding to valid SNPs is detailed in Table 2. Among these, the levels of Ceramide (d19:1/20:0), Ceramide (d19:1/24:0), Ceramide (d19:1/24:1), Ceramide (d19:1/18:0), Ceramide (d19:1/22:0), Ceramide (d18:1/24:1), Ceramide (d20:1/24:0), Total Ceramide, Ceramide [n(23)S(20)], Ceramide [n(24)DS(19)], Ceramide [n(24)DS(20)], Ceramide [n(25)S(20)], and Glycosyl-N-tricosanoyl-sphingadienine (d18:2/23:0) each showed a significant decrease in the risk of central precocious puberty (CPP) by 37.3 % (OR=0.627, 95 % CI 0.426–0.923, p=0.018), 31.9 % (OR=0.681, 95 % CI 0.487–0.951, p=0.024), 30.7 % (OR=0.693, 95 % CI 0.501–0.959, p=0.027), 41.7 % (OR=0.583, 95 % CI 0.361–0.942, p=0.027), 29.2 % (OR=0.708, 95 % CI 0.518–0.968, p=0.031), 49.5 % (OR=0.505, 95 % CI 0.259–0.984, p=0.045), 36.2 % (OR=0.638, 95 % CI 0.410–0.992, p=0.046), 45.0 % (OR=0.550, 95 % CI 0.309–0.980, p=0.042), 51.3 % (OR=0.487, 95 % CI 0.254–0.932, p=0.030), 40.5 % (OR=0.595, 95 % CI 0.372–0.950, p=0.030), 53 % (OR=0.470, 95 % CI 0.238–0.929, p=0.030), 54.1 % (OR=0.459, 95 % CI 0.228–0.927, p=0.030), and 56.4 % (OR=0.436, 95 % CI 0.191–0.992, p=0.048) for each standard deviation (SD) increase. In contrast, the levels of Ceramide (d17:1/20:0), Ceramide (d17:1/22:0), Ceramide (d17:1/24:0), and Ceramide (d18:1/14:0, d16:1/16:0) were associated with an increase in the risk of CPP by 161.8 % (OR=2.618, 95 % CI 1.168–5.867, p=0.019), 176.9 % (OR=2.769, 95 % CI 1.158–6.619, p=0.022), 168.7 % (OR=2.687, 95 % CI 1.153–6.261, p=0.022), and 237.7 % (OR=3.377, 95 % CI 1.100–10.366, p=0.033) for each SD increase. The other two methods of MR analysis showed similar directional trends, but not all results were significant (Table S2). When applying the Benjamini-Hochberg method to adjust for multiple comparisons between ceramide classes, none of the results reached the FDR-corrected significance threshold (p_adj<5.56 × 10−3). However, it is important to note that the findings in this exploratory study present suggestive evidence, with p_adj values ranging from 5.56 × 10−3 to 0.05.

Figure 2: MR analysis results of the effects of ceramide levels in blood on CPP in the database.
Figure 2:

MR analysis results of the effects of ceramide levels in blood on CPP in the database.

Table 2:

Summary of instrumental variables used for all significant causal association evidence in the database.

SNP Chr Pos EA OA Beta Se p-Value Palindromic mr_keep EAF F PMID
Total ceramide levels 35,668,104
rs168622 20 12,966,089 G T −0.33 0.022 7.34193E-51 FALSE TRUE 0.610 221
rs7412 19 45,412,079 T C −0.290 0.040 4.16772E-13 FALSE TRUE 0.090 61
Ceramide (d17:1/20:0) levels 35,668,104
rs17101394 14 64,232,386 A G 0.250 0.030 7.85975E-17 FALSE TRUE 0.160 74
rs7248003 19 8,301,048 T C 0.150 0.025 1.97318E-09 FALSE TRUE 0.710 41
rs7412 19 45,412,079 T C −0.250 0.040 4.10453E-10 FALSE TRUE 0.090 45
Ceramide (d17:1/22:0) levels 35,668,104
rs17101394 14 64,232,386 A G 0.330 0.029 5.30173E-30 FALSE TRUE 0.160 128
Ceramide (d17:1/24:0) levels 35,668,104
rs17101394 14 64,232,386 A G 0.340 0.029 9.58721E-32 FALSE TRUE 0.160 135
Ceramide (d18:1/24:1) levels 35,668,104
rs2076711 22 47,064,837 C A −0.160 0.025 1.55377E-10 FALSE TRUE 0.280 46
rs680379 20 12,969,400 G A −0.250 0.022 6.34475E-30 FALSE TRUE 0.600 131
rs7412 19 45,412,079 T C −0.230 0.040 8.92434E-09 FALSE TRUE 0.090 39
Ceramide (d19:1/20:0) levels 35,668,104
rs6520049 22 46,996,309 T C −0.140 0.025 2.14E-08 FALSE TRUE 0.270 34
rs680379 20 12,969,400 G A −0.520 0.021 2.31E-135 FALSE TRUE 0.600 670
Ceramide (d19:1/18:0) levels 35,668,104
rs168622 20 12,966,089 G A −0.430 0.021 3.51065E-93 FALSE TRUE 0.610 360
Ceramide (d19:1/22:0) levels 35,668,104
rs116940708 9 94,738,467 G A −0.460 0.074 5.09286E-10 FALSE TRUE 0.027 49
rs2423713 20 12,881,846 A G 0.150 0.026 7.96342E-09 FALSE TRUE 0.770 35
rs364585 20 12,962,718 G A −0.620 0.020 5.3905E-211 FALSE TRUE 0.610 671
rs6138379 20 24,789,626 A G 0.130 0.023 1.58431E-08 FALSE TRUE 0.330 33
Ceramide (d19:1/24:0) levels 35,668,104
rs2423713 20 12,881,846 A G 0.150 0.026 7.96342E-09 FALSE TRUE 0.770 35
rs364585 20 12,962,718 G A −0.590 0.021 1.12E-173 FALSE TRUE 0.610 620
rs75431233 9 94,781,894 A G −0.440 0.074 2.74865E-09 FALSE TRUE 0.027 45
Ceramide (d19:1/24:1) levels 35,668,104
rs116940708 9 94,738,467 G A −0.460 0.075 8.60566E-10 FALSE TRUE 0.027 49
rs364585 20 12,962,718 G A −0.620 0.020 5.3905E-211 FALSE TRUE 0.610 671
Ceramide (d20:1/24:0) levels 35,668,104
rs168622 20 12,966,089 G T −0.440 0.021 1.78481E-97 FALSE TRUE 0.610 375
rs8119743 20 13,120,092 A G 0.210 0.033 1.97032E-10 FALSE TRUE 0.120 41
Ceramide [n(23)S(20)] levels 33,437,986
rs1321940 20 12,959,885 A G 0.317 0.048 4.62E-11 FALSE TRUE 0.366 576
Ceramide [n(24)DS(19)] levels 33,437,986
rs1321940 20 12,959,885 A G 0.440 0.047 3.14E-21 FALSE TRUE 0.366 575
Ceramide [n(24)DS(20)] levels 33,437,986
rs680379 20 12,969,400 A G 0.302 0.047 1.48E-10 FALSE TRUE 0.368 581
Ceramide [n(25)S(20)] levels 33,437,986
rs680379 20 12,969,400 A G 0.294 0.048 9.18E-10 FALSE TRUE 0.368 580
Glycosyl-N-tricosanoyl-sphingadienine (d18:2/23:0) levels 36,635,386
rs10762405 10 70,808,679 G A 0.108 0.0175 7.49074E-10 FALSE TRUE 0.306 36
rs2381400 9 35,776,422 A G 0.103 0.0178 6.39868E-09 FALSE TRUE 0.291 32
rs9790720 4 47,552,471 A T 0.226 0.0189 4.93315E-33 TRUE TRUE 0.237 136
Ceramide (d18:1/14:0, d16:1/16:0) levels 36,635,386
rs7160525 14 63,765,502 A G 0.258 0.0217 9.17091E-33 FALSE TRUE 0.169 139

  1. SNP, single nucleotide polymorphisms; Chr, chromosome; Pos, position; EA, effect allele; OA, other allele; SE, standard error; EAF, effect allele frequency; F, F-statistic.

Evaluation of heterogeneity and horizontal pleiotropy, and power

Supplementary Table S2 presents the MR-PRESSO, MR-Egger intercept, and Cochrane Q test results, confirming no evidence of horizontal pleiotropy across all analyses (p>0.05). Cochrane Q tests further indicated no heterogeneity among the selected SNPs (p>0.05). Although funnel plots lacked significant symmetry due to the limited number of IVs (Supplementary Figure S1), the overall results support the robustness of the causal relationship. As shown in Supplementary Table S3, the total ceramide levels and 16 subclasses appeared underpowered due to the scarcity of CPP cases and the strict criteria for selecting IVs.

Metabolic pathway analysis

In the forward MR analysis, we employed the VEP annotation tool to identify gene symbols linked to the SNPs. GO analysis highlighted pathways such as ceramide biosynthesis, sphingolipid biosynthesis, and ceramide metabolism, with key genes like SPTLC1, SPTLC3, and CERS4 playing crucial roles in these processes (Figure 3A). KEGG pathway analysis identified five enriched functional pathways (Figure 3B), with strong associations in sphingolipid metabolism and signaling pathways, underscoring their potential importance in CPP.

Figure 3: Enrichment analysis. (A) GO analysis network graph. The graph shows the relationships between enriched GO terms, where node size represents the number of genes and color indicates significance. (B) KEGG analysis. Bar length corresponds to the number of genes involved in each pathway, and color denotes adjusted significance levels.
Figure 3:

Enrichment analysis. (A) GO analysis network graph. The graph shows the relationships between enriched GO terms, where node size represents the number of genes and color indicates significance. (B) KEGG analysis. Bar length corresponds to the number of genes involved in each pathway, and color denotes adjusted significance levels.

Discussion

In this study, we utilized GWAS data to investigate associations between total ceramide levels and 16 subclasses from an established pool of blood ceramides with CPP. Among the identified types, total ceramide levels and 12 specific subclasses demonstrated a protective effect associated with reduced risk of CPP. These include Ceramide (d19:1/20:0), Ceramide (d19:1/24:0), Ceramide (d19:1/24:1), Ceramide (d19:1/18:0), Ceramide (d19:1/22:0), Ceramide (d18:1/24:1), Ceramide (d20:1/24:0), Total Ceramide, Ceramide [n(23)S(20)], Ceramide [n(24)DS(19)], Ceramide [n(24)DS(20)], Ceramide [n(25)S(20)], and Glycosyl-N-tricosanoyl-sphingadienine (d18:2/23:0). In contrast, four subclasses were found to increase the risk of CPP, namely Ceramide (d17:1/20:0), Ceramide (d17:1/22:0), Ceramide (d17:1/24:0), and Ceramide (d18:1/14:0, d16:1/16:0). Various sensitivity analysis methods further validated these findings.

Ceramides are a large family of bioactive lipid signaling molecules with prominent roles in metabolic regulation and cellular processes such as growth, differentiation, and apoptosis. Emerging evidence suggests that ceramides are key mediators in various metabolic disorders and function as crucial modulators of leptin and ghrelin, two hormones central to metabolism and pubertal onset [31], 32]. Increased hypothalamic ceramide levels interfere with leptin’s anorectic effects while leptin itself inhibits ceramide synthesis, establishing a complex feedback loop [33]. Conversely, ghrelin promotes ceramide production, and blocking ceramide synthesis within the hypothalamus disrupts ghrelin’s appetite-stimulating actions [34]. This interplay aligns with the leptin-mTOR-Kisspeptin axis, as research by Kim et al. reveals that C16-ceramide negatively regulates mTOR, while sphingosine-1-phosphate (S1p), a ceramide metabolite, enhances mTOR signaling [35]. Additionally, hypothalamic ceramide plays a critical role in regulating the HPG axis at reproductive levels – extending beyond its metabolic function related to central estradiol (E2), which induces negative energy balance by mitigating ceramide-induced lipotoxicity and endoplasmic reticulum stress [36]. Heras et al. identified a novel non-classical pathway involving ceramide-controlled ovarian sympathetic innervation within the paraventricular nucleus of the hypothalamus as a new mediator contributing to the obesity-induced acceleration of puberty in female rats [7]. Moreover, a growing body of literature has identified that sphingolipids, including ceramides, sphingosine, S1p, sphingomyelin, and gangliosides, also play indispensable roles in steroid hormone biosynthesis, impacting both gene expression and signaling cascades involved in steroidogenesis [37].

In addition, studies have shown that the S1p/S1PR1/ceramide axis, in particular, has been implicated in hunger regulation within the hypothalamus, promoting lipolysis and energy expenditure while reducing lipogenesis, resulting in an anti-obesity effect that may have implications for metabolic and reproductive health [38]. Although previous lipidomic studies have found that phosphocholine(16:1(9Z)/16:1(9Z)) may be a potential biomarker for CPP, confounding factors such as BMI, diet and other life characteristics have not been controlled [39]. Recent findings indicate that certain ceramides, such as Cer18:0/15:0, Cer18:1/16:0, and Cer18:1/26:0, may distinguish CPP girls from controls, though observational limitations persist [8]. Furthermore, a longitudinal lipidomic study in children revealed persistent alterations in plasma ceramide levels associated with maternal obesity, suggesting their potential as early predictors of metabolic risk in offspring [40]. Another longitudinal metabolomic study found that the expression of PE[19:1(9Z)0:0] was elevated in female infants with CPP but decreased after treatment, indicating the possible utility of lipid metabolites in evaluating therapeutic efficacy [41]. Beyond blood-based findings, intestinal microbial metabolomics have also provided insights. Huang et al. reported that nitric oxide synthesis and Streptococcus abundance were closely related to CPP based on 16 S rRNA sequencing and non-targeted metabolomics [42]. In contrast, another fecal metabolomics study in girls with CPP and corresponding animal models identified thymine and inosine as differential metabolites compared with prepubertal controls [43]. Moreover, metabolomic analysis of mouse hypothalamic tissue revealed that (S)-abscisic acid, methylmalonic acid, and two-oxo-4-methylthiobutyric acid were significantly altered in the CPP group [44]. Overall, metabolomic studies in pediatric endocrinology remain limited, while some findings suggest an association between ceramides and CPP, the causative role of ceramides is still ambiguous. Future research is critical to elucidate the underlying mechanisms, particularly in non-obese settings, to clarify ceramide’s broader role in pubertal timing and identify potential therapeutic interventions.

A primary strength of this study is the demonstration of a suggestive causal link between the two. We have found a suggestive causal relationship between overall blood levels and specific subclasses of ceramide and CPP, though several of classes differs from trends observed in metabolic diseases like obesity. This discrepancy may be partially due to the distinct subcellular sites where ceramides are synthesized and their specific, poorly understood transport mechanisms. Sphingolipid levels within cells are precisely regulated by enzymes that localize to distinct subcellular compartments, thus controlling ceramide homeostasis in specific microenvironments [45]. Further, the biological impact of ceramides varies among subclasses. While certain ceramides are implicated in metabolic diseases, others may have protective roles. For instance, C24:1 ceramide levels, which are reduced in liver, heart, and plasma in type 1 diabetes and high-fat diet models, show beneficial effects when restored, improving glucose tolerance, insulin sensitivity, and fatty acid oxidation [46]. Similarly, elevated liver C18:1 ceramide levels, as induced by alkaline ceramidase (Acer3) inhibition, mitigate oxidative stress and reduce nonalcoholic steatohepatitis severity [47]. A longitudinal bi-racial cohort study also found that the mean levels of plasma monounsaturated ceramide and sphingolipid in prediabetic progressors were significantly reduced after adjusting for various factors such as age, gender, race/ethnicity, and BMI [48]. This finding is consistent with Floegel et al.’s prospective study on the association between serum metabolites and type 2 diabetes, which highlighted the protective effect of baseline levels of C16:1 sphingomyelin against diabetes [49]. Elevated levels of saturated sphingolipids and lower monounsaturated forms are linked to higher prediabetes risk, supporting recommendations to replace saturated fats with unsaturated fats to improve metabolic health [50], 51]. Collectively, these observations underscore the significance of distinguishing ceramide subclasses, backbones, and metabolites, alongside their subcellular distribution, in metabolic disease contexts.

In addition, GO and KEGG enrichment analyses identified three plausible genes and two potentially significant metabolic pathways associated with CPP. The identified genes include SPTLC1, SPTLC3, and CERS4, while the pathways are involved in sphingolipid metabolism and sphingolipid signaling transduction. The serine palmitoyltransferase genes SPTLC1 and SPTLC3 are pivotal in sphingolipid synthesis, and plasma ceramide levels are modulated by their enzymatic activity. In animal studies, increased SPTLC1 expression and elevated ceramide levels in the hypothalamic paraventricular nucleus are linked to early puberty in obese female rats [52], 53]. At the same time, CERS4 plays an important role in regulating sphingolipid types and metabolic balance. According to Kim et al., inhibition of CERS4 expression improves liver metabolic characteristics in mice [54]. In addition, CERS4 can produce C20 and C22 ceramides, which have protective effects in the development of heart failure [55]. Further research is needed to fully understand the roles of SPTLC3 and CerS4 in the occurrence of CPP. Overall, disruptions in bioactive sphingolipid signaling likely serve as both root causes and linking factors between metabolic diseases and their pathological consequences. Interventions targeting key enzymes or metabolic pathways, as described above, hold promise for future breakthroughs in diagnostics, therapeutics, and fundamental understanding of CPP.

The research exhibits several key advantages and distinctive characteristics, as outlined below. Primarily, we leveraged genetic instruments as proxies for blood ceramide levels and applied rigorous methodologies to mitigate potential violations of MR assumptions, thereby reducing bias and minimizing confounding factors. This study also significantly reduced potential biases caused by population stratification by limiting the data to participants of European ancestry. Sensitivity analyses reinforced the reliability of our results across different conditions and assumptions. Additionally, by constructing an extensive ceramide dataset, we enabled more comprehensive comparative analyses, bolstering the robustness of our findings. These specific ceramides with established suggestive causal links may serve as clues to promising therapeutic targets. This study also highlights several metabolic pathways potentially implicated in CPP development, suggesting new avenues for early identification and prevention of CPP in clinical settings.

Despite these strengths, there are several limitations to our study. First, the genetic data were derived solely from blood samples. Although we attempted to source cerebrospinal fluid metabolite data via public GWAS databases, we could not obtain suitable genetic instruments. Second, the GWAS data for both exposure and outcomes were sourced from European populations, which may limit the generalizability of our conclusions across diverse ethnic groups. Additionally, the incidence of idiopathic CPP in women is 5–10 times that of men, making it essential to distinguish sex-specific mechanisms in CPP etiology [56]. However, we were unable to obtain sufficient information to conduct a subgroup analysis to explore potential sex differences in ceramide levels. Furthermore, the MR analysis had limited statistical power, likely due to the case–control imbalance in the FinnGen Consortium’s CPP dataset. To address this limitation, we performed multiple sensitivity analyses, including MR-PRESSO, MR-Egger regression, andthe Cochrane Q test, all of which supported the robustness of the results. Nevertheless, these findings should be interpreted with caution and validated in future studies with larger sample sizes and more cases. Finally, while this study demonstrates a suggestive association between various ceramide species and CPP, the underlying mechanism for this association remains unclear. Further research, including functional or experimental validation, is necessary to elucidate their precise roles in CPP pathogenesis.

Conclusions

This two-sample Mendelian randomization study supports a suggestive causal relationship between ceramide and CPP. The overall and specific subtype levels of ceramide in plasma have great potential as objective indicators for evaluating potential protective or risk factors for the development of CPP in children. Our findings provide valuable evidence of ceramide’s impact on CPP, offering insights into new diagnostic and preventive approaches. Moreover, interventions targeting ceramide levels or correcting their imbalances hold promise for CPP management, though further studies are necessary to validate these findings and explore therapeutic applications.

Corresponding author: Xin Li, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China, E-mail:

Acknowledgments

We acknowledge the use of publicly available genome-wide summary statistics from the FinnGen Consortium (R11) and data derived from studies published in Nature Communications, Human Molecular Genetics, and Nature Genetics. Specifically, we utilized data on ceramide traits and central precocious puberty, as detailed in the respective studies led by Cadby G (Nat Commun, 2022), McGurk KA (Hum Mol Genet, 2021), Chen Y (Nat Genet, 2023), and Ottensmann L (Nat Commun, 2023). We are grateful to all consortia and authors for making their data publicly available and to the participants of these studies for their invaluable contributions.

  1. Funding information: This research received no external funding.

  2. Author contribution: D.G. and X.L.: contributed to the study design and manuscript writing; X.N. and Y.Z.: performed data analysis; C.W. and Y.L.: contributed to data acquisition and proofreading; Y.L. and D.G.: polished and revised the overall article. All authors have read and agreed to the published version of the manuscript.

  3. Conflict of interest: The authors declare no conflicts of interest.

  4. Data Availability Statement: The original contributions presented in the study are included in the article/Supplementary Mate-rials, further inquiries can be directed to the corresponding author.

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Supplementary Material

This article contains supplementary material (https://10.1515/med-2025-1337)

Received: 2025-01-20
Accepted: 2025-10-20
Published Online: 2025-12-17

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  204. Research progress on autophagy and its roles in sepsis induced organ injury
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  228. Letter to the Editor
  229. Role of enhanced external counterpulsation in long COVID
  230. Expression of Concern
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  234. Corrigendum
  235. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  236. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  237. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  238. Retraction
  239. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  240. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  241. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  242. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  243. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  244. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
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  247. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  248. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  249. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  250. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  251. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  252. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  253. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  254. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  255. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  256. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  257. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  258. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  259. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  260. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  261. A review of brain research on T2DM-related cognitive dysfunction
  262. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  263. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  264. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
https://doi.org/10.1515/med-2025-1337
Keywords for this article
ceramide; central precocious puberty; mendelian randomization; blood metabolites; sphingolipid
Creative Commons
BY 4.0

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  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
  128. Nucleotide metabolic abnormalities in post-COVID-19 condition and type 2 diabetes mellitus patients and their association with endocrine dysfunction
  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
  130. Ultrasound-guided unilateral versus bilateral erector spinae plane block for postoperative analgesia of patients undergoing laparoscopic cholecystectomy
  131. Profiling gut microbiome dynamics in subacute thyroiditis: Implications for pathogenesis, diagnosis, and treatment
  132. Delta neutrophil index, CRP/albumin ratio, procalcitonin, immature granulocytes, and HALP score in acute appendicitis: Best performing biomarker?
  133. Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
  134. H2valdien3 arrests the cell cycle and induces apoptosis of gastric cancer
  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Association of SGLT2 inhibition with psychiatric disorders: A Mendelian randomization study
  137. Motivational interviewing for alcohol use reduction in Thai patients
  138. Luteolin alleviates oxygen-glucose deprivation/reoxygenation-induced neuron injury by regulating NLRP3/IL-1β signaling
  139. Polyphyllin II inhibits thyroid cancer cell growth by simultaneously inhibiting glycolysis and oxidative phosphorylation
  140. Relationship between the expression of copper death promoting factor SLC31A1 in papillary thyroid carcinoma and clinicopathological indicators and prognosis
  141. CSF2 polarized neutrophils and invaded renal cancer cells in vitro influence
  142. Proton pump inhibitors-induced thrombocytopenia: A systematic literature analysis of case reports
  143. The current status and influence factors of research ability among community nurses: A sequential qualitative–quantitative study
  144. OKAIN: A comprehensive oncology knowledge base for the interpretation of clinically actionable alterations
  145. The relationship between serum CA50, CA242, and SAA levels and clinical pathological characteristics and prognosis in patients with pancreatic cancer
  146. Identification and external validation of a prognostic signature based on hypoxia–glycolysis-related genes for kidney renal clear cell carcinoma
  147. Engineered RBC-derived nanovesicles functionalized with tumor-targeting ligands: A comparative study on breast cancer targeting efficiency and biocompatibility
  148. Relationship of resting echocardiography combined with serum micronutrients to the severity of low-gradient severe aortic stenosis
  149. Effect of vibration on pain during subcutaneous heparin injection: A randomized, single-blind, placebo-controlled trial
  150. The diagnostic performance of machine learning-based FFRCT for coronary artery disease: A meta-analysis
  151. Comparing biofeedback device vs diaphragmatic breathing for bloating relief: A randomized controlled trial
  152. Serum uric acid to albumin ratio and C-reactive protein as predictive biomarkers for chronic total occlusion and coronary collateral circulation quality
  153. Multiple organ scoring systems for predicting in-hospital mortality of sepsis patients in the intensive care unit
  154. Single-cell RNA sequencing data analysis of the inner ear in gentamicin-treated mice via intraperitoneal injection
  155. Suppression of cathepsin B attenuates myocardial injury via limiting cardiomyocyte apoptosis
  156. Influence of sevoflurane combined with propofol anesthesia on the anesthesia effect and adverse reactions in children with acute appendicitis
  157. Identification of hub genes related to acute kidney injury caused by sevoflurane anesthesia and endoplasmic reticulum stress
  158. Efficacy and safety of PD-1/PD-L1 inhibitors in pancreatic ductal adenocarcinoma: a systematic review and Meta-analysis of randomized controlled trials
  159. The value of diagnostic experience in O-RADS MRI score for ovarian-adnexal lesions
  160. Health education pathway for individuals with temporary enterostomies using patient journey mapping
  161. Serum TLR8 as a potential diagnostic biomarker of coronary heart disease
  162. Intraoperative temperature management and its effect on surgical outcomes in elderly patients undergoing lichtenstein unilateral inguinal hernia repair
  163. Immunohistochemical profiling and neuroepithelial heterogeneity in immature ovarian teratomas: a retrospective digital pathology-based study
  164. Associated risk factors and prevalence of human papillomavirus infection among females visiting tertiary care hospital: a cross-sectional study from Nepal
  165. Comparative evaluation of various disc elution methods for the detection of colistin-resistant gram-negative bacteria
  166. Effect of timing of cholecystectomy on weight loss after sleeve gastrectomy in morbidly obese individuals with cholelithiasis: a retrospective cohort study
  167. Causal association between ceramide levels and central precocious puberty: a mendelian randomization study
  168. Novel predictive model for colorectal liver metastases recurrence: a radiomics and clinical data approach
  169. Relationship between resident physicians’ perceived professional value and exposure to violence
  170. Multiple sclerosis and type 1 diabetes: a Mendelian randomization study of European ancestry
  171. Rapid pathogen identification in peritoneal dialysis effluent by MALDI-TOF MS following blood culture enrichment
  172. Comparison of open and percutaneous A1 pulley release in pediatric trigger thumb: a retrospective cohort study
  173. Impact of combined diaphragm-lung ultrasound assessment on postoperative respiratory function in patients under general anesthesia recovery
  174. Development and internal validation of a nomogram for predicting short-term prognosis in ICU patients with acute pyelonephritis
  175. The association between hypoxic burden and blood pressure in patients with obstructive sleep apnea
  176. Promotion of asthenozoospermia by C9orf72 through suppression of spermatogonia activity via fructose metabolism and mitophagy
  177. Review Articles
  178. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  179. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  180. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  181. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  182. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  183. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  184. The application of augmented reality in robotic general surgery: A mini-review
  185. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  186. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  187. Plant polyphenols, terpenes, and terpenoids in oral health
  188. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  189. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  190. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  191. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  192. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  193. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  194. Giant borderline ovarian tumours – review of the literature
  195. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  196. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  197. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  198. Supplement strategies for infertility in overweight women: Evidence and legal insights
  199. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  200. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  201. Protective role of selenium in sepsis: Mechanisms and potential therapeutic strategies
  202. Strategies for hyperkalemia management in dialysis patients: A systematic review
  203. C-reactive protein-to-albumin ratio in peripheral artery disease
  204. Research progress on autophagy and its roles in sepsis induced organ injury
  205. Neuronutrition in autism spectrum disorders
  206. Pumilio 2 in neural development, function, and specific neurological disorders
  207. Antibiotic prescribing patterns in general dental practice- a scoping review
  208. Clinical and medico-legal reflections on non-invasive prenatal testing
  209. Smartphone use and back pain: a narrative review of postural pathologies
  210. Targeting endothelial oxidative stress in hypertension
  211. Exploring links between acne and metabolic syndrome: a narrative review
  212. Case Reports
  213. Delayed graft function after renal transplantation
  214. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  215. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  216. Giant right atrial hemangioma presenting with ascites: A case report
  217. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  218. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  219. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  220. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  221. Combined VAT and retroperitoneoscopy for pleural empyema due to nephro-pleuric fistula in xanthogranulomatous pyelonephritis
  222. A rare case of Opalski syndrome with a suspected multiple sclerosis etiology
  223. Newly diagnosed B-cell acute lymphoblastic leukemia demonstrating localized bone marrow infiltration exclusively in the lower extremities
  224. Rapid Communication
  225. Biological properties of valve materials using RGD and EC
  226. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  227. Repeat influenza incidence across two consecutive influenza seasons
  228. Letter to the Editor
  229. Role of enhanced external counterpulsation in long COVID
  230. Expression of Concern
  231. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  232. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  233. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  234. Corrigendum
  235. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  236. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  237. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  238. Retraction
  239. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  240. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  241. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  242. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  243. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  244. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  245. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  246. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  247. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  248. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  249. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  250. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  251. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  252. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  253. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  254. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  255. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  256. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  257. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  258. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  259. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  260. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  261. A review of brain research on T2DM-related cognitive dysfunction
  262. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  263. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  264. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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