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

Area of Science:

• Hepatology
• Microbiology
• Oncology

Background:

• Metabolic associated fatty liver disease (MAFLD) is increasingly linked to hepatocellular carcinoma (HCC).
• High-fat diet (HFD)-induced gut dysbiosis is implicated in MAFLD progression.
• Understanding the molecular mechanisms driving MAFLD-HCC is critical.

Purpose of the Study:

• To investigate the role of gut dysbiosis and hepatic IGSF9 in MAFLD-related HCC.
• To identify potential therapeutic targets for MAFLD-HCC.

Main Methods:

• Utilized high-fat diet (HFD) induced mouse models of MAFLD.
• Investigated the gut microbiome composition, focusing on *Enterococcus faecalis* enrichment.
• Assessed hepatic IGSF9 expression and its interaction with C1q and ubiquitin ligases.
• Evaluated therapeutic interventions including *Bifidobacterium pseudolongum* supplementation, IGSF9 overexpression, and C1q neutralization.

Main Results:

• HFD induced gut dysbiosis, enriching *Enterococcus faecalis*, which suppressed hepatic IGSF9 expression.
• Reduced IGSF9 expression exacerbated liver injury, steatosis, fibrosis, and HCC susceptibility.
• Low hepatic IGSF9 levels correlated with poor prognosis in MAFLD-HCC patients.
• IGSF9 deficiency led to C1q accumulation, accelerating MAFLD progression.
• *B. pseudolongum* supplementation, IGSF9 overexpression, and C1q neutralization prevented MAFLD-HCC progression in preclinical models.

Conclusions:

• The *E. faecalis*/IGSF9/C1q axis is implicated in MAFLD-HCC pathogenesis.
• IGSF9 functions as a tumor suppressor by degrading C1q.
• IGSF9 may serve as a prognostic biomarker and therapeutic target for MAFLD-HCC.