Microbiota-derived HS Induces C-kit CDC1 Autophagic Cell Death and Liver Inflammation in Metabolic Dysfunction-associated Steatohepatitis

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 HS-producing Desulfovibrio_sp. Transplanting of MASH-derived fecal flora, Desulfovibrio_sp., or injecting HS intraperitoneally into MASLD mice decreases the c-kitcDC1 population and exacerbates liver inflammation. Mechanistically, HS 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 HS triggers the autophagic cell death of c-kit cDC1 and ignites the liver inflammatory cascade in MASH.