Microbiota-derived H2S induces c-kit+ cDC1 autophagic cell death and liver inflammation in metabolic dysfunction-associated steatohepatitis

作者：Yuxiang Song, Na Li, Shang Jiang, Kexin Wang, Guoyue Lv, Zhongqi Fan, Xiliang Du, Wenwen Gao, Lin Lei, Zhe Wang, Guowen Liu, Xinwei Li · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-57574-3 · 被引用次数：15 · 研究领域：Liver Disease Diagnosis and Treatment、Diet, Metabolism, and Disease、Pancreatitis Pathology and Treatment

Immune dysregulation-induced inflammation serves as a driving force in the progression of metabolic dysfunction-associated steatohepatitis (MASH), while the underlying cellular and molecular mechanisms remain largely uncharted. A Western diet (WD) is employed to construct mouse models of metabolic dysfunction associated steatotic liver disease (MASLD) or MASH. Mass cytometry identifies a c-kit+ cDC1 subset whose frequency is reduced in the livers of mice and patients with MASH compared with healthy controls. Adoptive cell transfer of c-kit+ cDC1 protects the progression of MASH. Moreover, analysis of gut microbe sequence shows that WD-fed mice and MASLD/MASH patients exhibit gut microbiota dysbiosis, with an elevated abundance of H2S-producing Desulfovibrio_sp. Transplanting of MASH-derived fecal flora, Desulfovibrio_sp., or injecting H2S intraperitoneally into MASLD mice decreases the c-kit+cDC1 population and exacerbates liver inflammation. Mechanistically, H2S induces autophagic cell death of cDC1 in a c-kit-dependent manner in cDC-specific c-kit-/- and Atg5-/- mice. We thus uncover that microbiota-derived H2S triggers the autophagic cell death of c-kit+ cDC1 and ignites the liver inflammatory cascade in MASH. The immune regulatory mechanism for metabolic dysfunction-associated steatohepatitis (MASH) remains elusive. Here, the authors identify a c-kit+ cDC1 subset, which can be depleted by Desulfovibrio_sp.-induced H2S via autophagic cell death and contributing to uncontro...