GP73 inhibition alleviates hepatic fibrosis by suppressing TGF-β/mTOR signaling pathways.

Hepatic fibrosis, a hallmark of chronic liver diseases, arises from persistent activation of hepatic stellate cells (HSCs). Golgi protein 73 (GP73) is a recognized fibrosis biomarker, yet its active role in driving fibrogenesis and the underlying molecular mechanisms remain poorly defined. Using wild-type, GP73 knockout, and knock-in mouse models, we demonstrate that GP73 expression is not merely a marker but a key functional modulator of fibrotic progression, correlates strongly with fibrosis severity. While these genetic models do not develop spontaneous hepatic fibrosis under basal conditions-notwithstanding the potential metabolic roles of GP73-our results demonstrate that GP73 expression levels significantly dictate the severity of CCl4-induced fibrotic progression. Mechanistically, endogenous co-immunoprecipitation (Co-IP) revealed that GP73 physically interacts with TGF-β receptor 1 (TGFBR1), mTOR, and the recycling endosome marker Rab11. GP73 enhances HSC activation by amplifying TGF-β and mTOR signaling through the inhibition of key fibrotic factors' degradation, such as TGFBR1 and mTOR. Protein half-life and rescue experiments confirmed that GP73 prevents the lysosomal degradation of TGFBR1 and mTOR; notably, re-introducing GP73 into knockdown cells successfully restored receptor stability and downstream signaling. Furthermore, pharmacological disruption of endocytic trafficking with Brefeldin A (BFA) abolished the protective effect of GP73, leading to accelerated receptor degradation. Suppressing GP73 reduced HSC activation and attenuated collagen deposition in vivo. Our findings identify GP73 as a molecular scaffold that reroutes fibrotic signaling complexes into the recycling pathway and away from degradation. Consequently, our results position GP73-mediated endocytic recycling as a potential therapeutic target and a viable adjunctive strategy for managing chronic liver diseases.