Quantitative proteomics analysis of liver from LONP1 Knockout mice

The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis remains largely unknow. Here, we revealed a fibrosis related mechanism of hepatocytes-HSCs crosstalk regulated by hepatocyte LONP1. We demonstrate that hepatocyte LONP1 expression is decreased in HFD-fed mice and MASH patients. Liver-specific LONP1 deficiency increases orotic acid level and aggravates MASH-induced liver fibrosis in mice. We have identified DHODH as a substrate that is selectively degraded by LONP1 in an ATP-dependent manner. Moreover, activation of LONP1 reduces orotic acid levels and alleviates MASH-induced fibrosis in mice. Mechanistically, LONP1 mediates DHODH turnover, maintaining lower orotic acid levels to inhibit ATF3-mediated HSC proliferation and activation, thereby preventing liver fibrosis. Furthermore, plasma orotic acid levels are negatively correlated with liver LONP1 levels in humans. Therefore, targeting LONP1-mediated hepatocyte-HSC communication may represent a promising therapeutic strategy for MASH-induced liver fibrosis.