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

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.