Enterococcus faecalis impairs IGSF9-dependent C1q degradation to accelerate MAFLD-HCC progression

The global increase in metabolic associated fatty liver disease (MAFLD)-related hepatocellular carcinoma (HCC) necessitates urgent investigation of its underlying mechanisms. Our study reveals that high fat diet (HFD)-induced gut dysbiosis enriches Enterococcus faecalis, a potential carcinogenic bacterium. Mechanistically, which suppresses hepatic IGSF9 expression, exacerbating liver injury (elevated ALT/AST/ALP), steatosis, fibrosis, and HCC susceptibility. Clinically, reduced hepatic IGSF9 correlates with poor prognosis, particularly in MAFLD-HCC patients. Mechanistically, IGSF9 binds C1QC and E3 ubiquitin ligases (NEDD4/UBE3A) to promote C1QC ubiquitination and degradation; IGSF9 deficiency leads to pathogenic C1q accumulation, accelerating MAFLD progression. Importantly, early interventions targeting this axis - including Bifidobacterium pseudolongum supplementation, overexpressing IGSF9, and C1q neutralization - effectively prevented MAFLD-HCC progression in preclinical models. These findings provide preliminary evidence that the E. faecalis/IGSF9/C1q axis could be involved in MAFLD-HCC, with IGSF9 may serve as both a prognostic biomarker and therapeutic target, which worth further exploration in future studies.