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

Yuxiang Song, Na Li, Shang Jiang, Kexin Wang, Guoyue Lv, Zhongqi Fan, Xiliang Du, Wenwen Gao, Lin Lei, Zhe Wang, Guowen Liu and Xinwei Li ()
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Yuxiang Song: Jilin University
Na Li: Jilin University
Shang Jiang: Jilin University
Kexin Wang: Jilin University
Guoyue Lv: First Hospital of Jilin University
Zhongqi Fan: First Hospital of Jilin University
Xiliang Du: Jilin University
Wenwen Gao: Jilin University
Lin Lei: Jilin University
Zhe Wang: Jilin University
Guowen Liu: Jilin University
Xinwei Li: Jilin University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57574-3

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