TJ0113 attenuates fibrosis in metabolic dysfunction-associated steatohepatitis by inducing mitophagy.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a liver disease accompanied by inflammatory cell infiltration. There is growing evidence that insufficient mitophagy can exacerbate inflammation and liver fibrosis (LF). TJ0113 is a novel mitophagy inducer. The study aimed to explore the role of TJ0113 in ameliorating fibrosis in MASH and its mechanisms.

Methods: A high-fat diet (HFD)-induced MASH mice model and a transforming growth factor (TGF)-β1-induced LX-2 cells model were used, and then they were treated with TJ0113. Changes in hepatocyte damage were observed using electron microscopy. Expression of key molecules related to mitophagy, mitochondrial damage and inflammation in liver was detected by immunofluorescence staining (IF), immunohistochemistry (IHC) and western blotting (WB).

Result: TJ0113 induces mitophagy through parkin/PINK1 and ATG5 signaling pathways and reduces lipid accumulation, inflammation and fibrosis in the liver of MASH mice. TJ0113 attenuated hepatic injury and lowered serum ALT, AST, TC and TG levels. TJ0113 reduced pro-inflammatory factors (IL-1β, IL-6, TNF-α), TGF-β1/Smad pathway activation and typical fibrosis-related molecules (α-SMA, Collagen-1) expression. In addition, NF-κB/NLRP3 signaling pathway activation after MASH was significantly attenuated by enhanced Mitophagy. We found that TJ0113 was able to effectively and safely induce mitophagy in vitro and reduce TGF-β1/Smad signaling and downstream pro-fibrotic responses in TGF-β1-treated LX-2 cells.

Conclusion: TJ0113 enhances mitophagy to inhibit lipid accumulation, inflammation and fibrosis formation in MASH, and is a candidate for MASH treatment.