Diverse roles of ZEB1 in modulating inflammation: beyond EMT mechanisms

Chronic and acute inflammation serve as critical pathological foundations for numerous diseases [1]. Inflammatory cytokines, such as IL-6 and TNF-α, along with reactive oxygen species (ROS), can induce DNA damage and genetic mutations, thereby increasing cancer risk [2]. The transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) plays a central role in various biological processes, including embryonic development, inflammation, and cancer progression [3]. Moreover, ZEB1 is essential for regulating the function and polarization of immune cells, particularly macrophages. As key components of the immune system, macrophages contribute to tissue homeostasis, inflammation, and infection response [4]. Their polarization into distinct phenotypes, enabling them to perform diverse functions ranging from pathogen clearance to tumor initiation, is tightly controlled by ZEB1 [5, 6].

ZEB1 was initially identified as a transcription factor driving epithelial-mesenchymal transition (EMT). However, subsequent studies have revealed that ZEB1 contributes to various diseases through mechanisms beyond EMT [7] (Figure 1). For example, Zeb1 regulates macrophage plasticity in atherosclerotic plaques by promoting cholesterol efflux [8]. It also plays a key role in modulating the transition of bone marrow-derived macrophages into osteoclasts, which is crucial for the differentiation of monocyte precursors into preosteoclasts. This process involves Zeb1 binding to and controlling the expression of ATP-buffering mitochondrial creatine kinase 1 (MtCK1) [9]. Additionally, Zeb1 enhances the stemness features of macrophages following cytomegalovirus infection [10].

Figure 1:

The ZEB1 factor regulates the plasticity of macrophages under diverse conditions. ZEB1, zinc finger E-box-binding homeobox 1; EMT, epithelial-mesenchymal transition.

A recent study by Cortés et al. provides a comprehensive exploration of the role of ZEB1 in macrophage metabolic reprogramming and its dynamic regulation of inflammation using both mouse models and human samples [11]. This study highlights the dual functions of ZEB1 in macrophages under different pathological conditions. In models of LPS-induced acute inflammation, Zeb1 was shown to promote the expression of glycolysis-related genes (e.g., Slc2a1 and Hk2), enhance the secretion of the proinflammatory cytokine IL-6, and support the inflammatory response by increasing ROS production and mitochondrial activity. Conversely, in an immunosuppressive mouse model, ZEB1 drove macrophages toward an anti-inflammatory phenotype by suppressing mitochondrial protein translation and reducing mitochondrial content. This surprising discovery reveals that ZEB1 can play dual roles within the same pathological context – a phenomenon not previously reported. Moreover, these findings align with earlier studies suggesting that ZEB1 regulates macrophage metabolic reprogramming [12].

To investigate the potential link between Zeb1 and the anti-diabetic drug metformin, as well as the role of Zeb1 in macrophage-mediated chronic inflammation, the study first confirmed that metformin’s anti-inflammatory effects rely on Zeb1. Using a chronic inflammatory model of psoriasis induced by the TLR7/8 agonist imiquimod, the authors demonstrated that mice lacking Zeb1 exhibited more severe skin inflammation. In contrast, in Zeb1-expressing mice, metformin effectively alleviated inflammatory symptoms and reduced macrophage infiltration in the lesion area. These findings highlight the critical role of Zeb1 in chronic inflammation and its alignment with metformin’s anti-inflammatory mechanisms.

However, we believe there are still several questions that the study did not address. First, the findings primarily rely on mouse models, which may not fully replicate the complex pathology of human diseases. For instance, the LPS-induced inflammation model depends heavily on exogenous stimulation and may fail to reflect pathological processes driven by endogenous inflammatory triggers, such as tissue damage or metabolic disorders. Second, while the study demonstrated that Zeb1 regulates mitochondrial translation by inhibiting amino acid transport and mTORC1 signaling, it lacks a detailed analysis of how ZEB1 specifically and selectively interacts with metabolic and inflammation-related genes. Additionally, the role of ZEB1 in macrophages across different tissues (e.g., lungs, liver, and joints) was not investigated, making it challenging to determine its specific function in multi-organ inflammation. Furthermore, the study focused exclusively on macrophages and did not explore whether ZEB1 influences the metabolism and function of other immune cells, such as T cells and NK cells, potentially limiting the understanding of its broader immune regulatory mechanisms. Addressing these questions in future research could provide fascinating insights.