Complement factor D is a drug target for metabolic-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a globally prevalent disorder linked to metabolic syndrome, currently lacking approved therapies, and existing treatments offer only limited benefits. Complement factor D (CFD), a rate-limiting serine protease in the alternative complement pathway, has been suggested to be associated with metabolic diseases in previous studies. Its inhibitor, danicopan, is primarily used for paroxysmal nocturnal hemoglobinuria (PNH), but its role in metabolic liver diseases remains underexplored. Here, we assessed the role of CFD in MAFLD and danicopan therapy using HFD mice, patient sera, and hepatocytes via CRISPR knockout and pharmacological interventions. Key findings demonstrated significant upregulation of CFD in MAFLD mice livers and patient sera. Genetic CFD ablation attenuated hepatocyte lipid deposition. Danicopan reduced intracellular triglycerides/cholesterol, improved glucose tolerance, lowered ALT, and alleviated hepatic steatosis in obese mice without weight change. Mechanistically, danicopan suppressed NF-κB signaling, inhibiting lipid-related genes (CD36/FASN/ FATP2) and inflammatory mediators (MMP12/IL-6/TNF-α). These results establish CFD as a novel MAFLD mediator, validating FDA-approved danicopan's therapeutic efficacy and translational potential. This work provides critical evidence for targeting the CFD pathway in MAFLD management.