Alcoholic liver fibrosis (ALF) is a chronic liver disease caused by long-term excessive alcohol consumption. Increasing evidence indicates that ferroptosis is a key contributor to the development and progression of liver fibrosis; however, its precise molecular mechanisms in ALF remain unclear. In this study, we investigated the role of TRIM21 in regulating the ubiquitination of IDO1 to modulate ferroptosis and thereby alleviate ALF. An ALF mouse model was established using the Lieber-DeCarli ethanol diet combined with ethanol gavage for 8 weeks, and liver fibrosis was evaluated via histological staining, enzyme-linked immunosorbent assay, quantitative real-time PCR, and western blotting. Ethanol-treated LX-2 cells were used as an in vitro model to explore the molecular mechanism through IDO1 knockdown and TRIM21 overexpression experiments. Our results showed that ferroptosis plays a critical role in ALF progression, accompanied by upregulation of IDO1 and downregulation of TRIM21. IDO1 knockdown effectively inhibited ferroptosis, reduced reactive oxygen species accumulation, and suppressed hepatic stellate cell activation. Mechanistically, TRIM21 interacted with IDO1 and promoted its ubiquitination, resulting in reduced IDO1 protein levels and inhibition of ferroptosis, thereby alleviating ALF. In conclusion, TRIM21 alleviates ALF by promoting the ubiquitination of IDO1 to inhibit ferroptosis, suggesting that the TRIM21-IDO1 axis represents a promising therapeutic target for ALF treatment.
Zhong et al. (Sat,) studied this question.