Insulin-induced gene 2 alleviates ischemia-reperfusion injury in steatotic liver by inhibiting GPX4-dependent ferroptosis.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-04-01 DOI:10.1038/s41420-025-02406-y

Yichao Wu, Changbiao Li, Di Lu, Kangchen Chen, Renyi Su, Shengjun Xu, Fengqiang Gao, Zhengxing Lian, Fan Yang, Jun Chen, Fangqiang Wei, Xiao Xu, Zhikun Liu

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Abstract

Hepatic steatosis significantly elevates the vulnerability of the graft to ischemia-reperfusion (I/R) injury during liver transplantation (LT). We investigated the protective role of insulin-induced gene 2 (Insig2) in steatotic liver's I/R injury and underlying mechanisms. Employing mouse model with Insig2 knock-out or hepatocyte-specific overexpression and high-fat diets to induce steatosis, we subjected these mice to hepatic I/R injury. The primary hepatocytes isolated from steatotic liver were used in in vitro hypoxia/reoxygenation (H/R) experiment. Our integrated in vivo and in vitro approach uncovered that Insig2 deficiency exacerbated steatotic liver's damage following hepatic I/R injury, whereas its overexpression offers protection. Mechanically, integrative analysis of transcriptome, proteome, and metabolome found that Insig2 deficiency disturbed lipid metabolism and oxidative stress homeostasis, particularly inhibiting GPX4 expression to induce ferroptosis. Furthermore, chemical inhibition of ferroptosis reversed the deleterious effect of Insig2 deficiency; whereas the protective influence of Insig2 overexpression was negated by the target inhibition of GPX4, leading to an exacerbation of hepatic I/R damage. These insights underscored the potential of the Insig2-GPX4 axis as a therapeutic target, presenting a novel avenue for enhancing the resilience of steatotic liver grafts against I/R injury.

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.