Nuclear factor erythroid 2-related factor 2 ameliorates disordered glucose and lipid metabolism in liver: Involvement of gasdermin D in regulating pyroptosis

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2025-02-24 DOI:10.1002/ctm2.70233

Xuyun Xia, Qin Zhang, Xia Fang, Ling Li, Gangyi Yang, Xiaohui Xu, Mengliu Yang

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Abstract

Background

The epidemic of metabolic dysfunction-associated fatty liver disease linked to excessive high-fat diet (HFD) consumption has sparked widespread public concern. Nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to improve glucose/lipid metabolism, liver lipid degeneration and alleviate HFD-induced inflammation. However, its pathways and mechanisms of action are not fully understood.

Methods

To confirm the effect of NRF2 on glucose/lipid metabolism in the liver, Nrf2-/- mice as well as liver-specific Nrf2 knockout mice, and AAV-TBG-Nrf2 were employed. The hyperinsulinemic-euglycemic clamp was utilized to determine the effect of NRF2 on glucose metabolism. To elucidate the effect of NRF2 on pyroptosis, we performed western blots, immunofluorescence, quantitative real-time PCR, and Flow cytometry experiments. Finally, chromatin immunoprecipitation-seq and dual-luciferase reporter assay was used to underscore the transcriptional regulatory effect of NRF2 on Gsdmd.

Results

We found that overexpression of Nrf2 inhibited the expression of inflammatory cytokines and pyroptosis markers, including cle-Caspase1, NLRP3 and the N-terminus of gasdermin D (N-GSDMD) both in vivo and in vitro, while Nrf2 deficiency was the opposite. Specifically, with NRF2 expression up-regulated, GSDMD expression decreased and Gsdmd overexpression partially reversed the effect of Nrf2 overexpression on pro-inflammatory phenotype. Mechanistically, we demonstrate that NRF2 binds to the Gsdmd promoter at the −2110 - 1130 bp site, inhibiting the GSDMD expression and thereby improving glucose/lipid metabolism and liver steatosis.

Conclusion

Our data indicate that NRF2 is an effective inhibitor of pyroptosis and has a multi-target effect in the treatment of obesity-related metabolic diseases.

Key points

MAFLD is associated with increased hepatocytes NRF2 expression.
NRF2 alleviates MAFLD by suppressing pyroptosis.
NRF2 directly inhibits GSDMD expression to regulate pyroptosis.
Targeting the NRF2–pyroptosis (GSDMD) axis offers a potential therapeutic strategy for MAFLD.

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核因子红系2相关因子2改善肝脏糖脂代谢紊乱：气真皮蛋白D参与调节焦亡

背景与过度高脂肪饮食（HFD）有关的代谢功能障碍相关脂肪肝的流行引起了公众的广泛关注。核因子红细胞2相关因子2 （NRF2）已被报道改善糖/脂质代谢，肝脂质变性和减轻hfd诱导的炎症。然而，其作用途径和机制尚不完全清楚。方法采用NRF2 -/-小鼠、肝脏特异性NRF2敲除小鼠和AAV-TBG-Nrf2，验证NRF2对肝脏糖脂代谢的影响。采用高胰岛素-正糖钳法测定NRF2对糖代谢的影响。为了阐明NRF2对焦亡的影响，我们进行了western blots、免疫荧光、实时荧光定量PCR和流式细胞术实验。最后，采用染色质免疫沉淀-序列和双荧光素酶报告基因检测来强调NRF2对Gsdmd的转录调控作用。结果我们发现Nrf2过表达在体内和体外均能抑制炎性细胞因子和焦亡标志物的表达，包括cle-Caspase1、NLRP3和gasdermin D (N-GSDMD) n端，而Nrf2缺乏则相反。具体而言，随着NRF2表达上调，GSDMD表达降低，GSDMD过表达部分逆转了NRF2过表达对促炎表型的影响。在机制上，我们证明NRF2在- 2110 - 1130bp位点与Gsdmd启动子结合，抑制Gsdmd的表达，从而改善糖/脂代谢和肝脏脂肪变性。结论NRF2是一种有效的焦亡抑制剂，在治疗肥胖相关代谢疾病中具有多靶点效应。MAFLD与肝细胞NRF2表达升高相关。NRF2通过抑制焦亡来缓解MAFLD。NRF2直接抑制GSDMD表达调控焦亡。靶向nrf2 -焦亡（GSDMD）轴为MAFLD提供了一种潜在的治疗策略。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.