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GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver

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Abstract

Dysregulated metabolism, cell death, and inflammation contribute to the development of metabolic dysfunction-associated steatohepatitis (MASH). Pyroptosis, a recently identified form of programmed cell death, is closely linked to inflammation. However, the precise role of pyroptosis, particularly gasdermin-E (GSDME), in MASH development remains unknown. In this study, we observed GSDME cleavage and GSDME-associated interleukin-1β (IL-1β)/IL-18 induction in liver tissues of MASH patients and MASH mouse models induced by a choline-deficient high-fat diet (CDHFD) or a high-fat/high-cholesterol diet (HFHC). Compared with wild-type mice, global GSDME knockout mice exhibited reduced liver steatosis, steatohepatitis, fibrosis, endoplasmic reticulum stress, lipotoxicity and mitochondrial dysfunction in CDHFD- or HFHC-induced MASH models. Moreover, GSDME knockout resulted in increased energy expenditure, inhibited intestinal nutrient absorption, and reduced body weight. In the mice with GSDME deficiency, reintroduction of GSDME in myeloid cells—rather than hepatocytes—mimicked the MASH pathologies and metabolic dysfunctions, as well as the changes in the formation of neutrophil extracellular traps and hepatic macrophage/monocyte subclusters. These subclusters included shifts in Tim4+ or CD163+ resident Kupffer cells, Ly6Chi pro-inflammatory monocytes, and Ly6CloCCR2loCX3CR1hi patrolling monocytes. Integrated analyses of RNA sequencing and quantitative proteomics revealed a significant GSDME-dependent reduction in citrullination at the arginine-114 (R114) site of dynamin-related protein 1 (Drp1) during MASH. Mutation of Drp1 at R114 reduced its stability, impaired its ability to redistribute to mitochondria and regulate mitophagy, and ultimately promoted its degradation under MASH stress. GSDME deficiency reversed the de-citrullination of Drp1R114, preserved Drp1 stability, and enhanced mitochondrial function. Our study highlights the role of GSDME in promoting MASH through regulating pyroptosis, Drp1 citrullination-dependent mitochondrial function, and energy balance in the intestine and liver, and suggests that GSDME may be a potential therapeutic target for managing MASH.

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Fig. 1: Hepatic GSDME expression in MASH patients and mice.
Fig. 2: Global knockout of GSDME ameliorates steatosis and steatohepatitis in CDHFD-induced MASH mouse model.
Fig. 3: Global Knockout of GSDME mitigates liver fibrosis, ER stress and mitochondrial dysfunction in CDHFD-induced MASH mouse model.
Fig. 4: Impacts of rescuing GSDME gene transcription in different liver cell types on MASH development.
Fig. 5: Multiplexed Flow Cytometry Reveals the Regulatory Action of Myeloid GSDME on MΦ/MO Infiltration In MASH.
Fig. 6: GSDME controls energy homeostasis and intentisne nutrition absorption.
Fig. 7: MASH Promotes Loss of Drp1 R114 Citrullination, Which Is Reversed by GSDME Deletion.
Fig. 8: R114 Citrullination of Drp1 Is Critical for Its Stability and Mitochondrial Function.

Data availability

The Raw RNA-sequencing data was deposited in NCBI Sequence Read Archive (SRA) database (No. PRJNA1004734). The raw proteomic data was deposited in PRoteomics IDEntifications (PRIDE) database (No. PXD044559). Other data analyzed during this study are included in this published article and the Supplementary data files. Additional supporting data are available from the corresponding authors upon reasonable request.

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Funding

This work was supported by the grants from National Natural Science Foundation of China (82073915, 82373927, 82274030 and 8210453), Shanghai Science and Technology Commission (21XD1424900, 19140904700, 19140904900, 2019CXJQ03 and 21S11901200), Shanghai Shuguang Program (19SG32), Shanghai Municipal Three Year Action Plan for Strengthening the Construction of Public Health System (GWVI-11.2-XD06) and Outstanding Youth in Shanghai Skin Hospital (202172). We thank the patients and their families.

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Author notes

  1. These authors contributed equally: Jia-Hui Zhu, Shen-** Ouyang, Guo-Yan Zhang, Qi Cao, Rujuan **n.

Authors and Affiliations

  1. Department of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China

    Jia-Hui Zhu, Shen-** Ouyang, Guo-Yan Zhang, Hang Yin, **g-Wen Wu, Yan Zhang, Zhen Zhang, Yi Liu, Jie Tong, Fu-Ming Shen & Dong-Jie Li

  2. Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China

    Jia-Hui Zhu, Jiang-Tao Fu, Yi-Ting Chen & Jia-Bao Zhang

  3. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University, Shanghai, China

    Qi Cao, Jia-Bao Zhang & Pei Wang

  4. The National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University, Shanghai, China

    Qi Cao & Pei Wang

  5. Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China

    Rujuan **n

  6. Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University/Second Military Medical University, Shanghai, China

    Jian Liu

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  1. Jia-Hui Zhu
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Contributions

PW conceived and designed research; JHZ, SXO, QC, GYZ, JWW, YZ, JT, ZZ, YL, JTF, and HY performed experiments; JL provided patents samples; YTC, JT, HBZ, DJL and FMS analyzed data. JHZ, SXO, QC and PW wrote the manuscript. PW and JBZ provided funding. All authors contributed with productive discussions and knowledge to the final version of this manuscript.

Corresponding author

Correspondence to Pei Wang.

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The authors declare no competing interests.

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The ethical aspects for the human samples were reviewed and approved by the institutional research ethics committee of the Eastern Hepatobiliary Surgery Hospital (approval number: EHBHKY2020-K-045). The research was conducted in accordance with the ethical principles of the Helsinki Declaration. Informed consent was duly obtained from each participant included in the study. For the animal study, all experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Shanghai Tenth People’s Hospital of Tongji University (approval number: SHDSYY-2022-3019) and followed the Principles of Laboratory Animal Care published by the National Institutes of Health (NIH publication 86-23 revised 1985) and ARRIVE guidelines.

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Zhu, JH., Ouyang, SX., Zhang, GY. et al. GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01343-0

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