SerpinB1a induces hepatopulmonary syndrome by promoting CTSG/AMPK/mTOR pathway-mediated mitophagy.

Abstract

Mitophagy, as an important mechanism for selective removal of damaged mitochondria in cells, plays a crucial role in upholding cellular homeostasis. Mounting evidence suggests that autophagy is associated with lung disease. However, the potential molecular mechanisms affecting mitophagy are still obscure in hepatopulmonary syndrome (HPS) development. In this study, elevated SerpinB1a levels were detected in HPS patients' serum, showing a significant inverse correlation with arterial oxygen saturation. In the CBDL-induced rat HPS model, SerpinB1a knockdown attenuated pulmonary hemorrhage, microvascular dilation, and hepatic fibrosis. In vitro studies demonstrated that treatment of PMVECs with serum from HPS rats induced pathological proliferation, migration, and angiogenesis. Silencing of SerpinB1a effectively suppressed these aberrant cellular processes. Mechanistically, SerpinB1a promoted PMVEC dysfunction by interacting with and upregulating Cathepsin G (CTSG), thus activating the VEGF / AMPK / mTOR pathway and subsequent induction of mitophagy. In conclusion, SerpinB1a knockdown attenuated pulmonary microvascular dilation and HPS progression by inhibiting this CTSG/VEGF/AMPK/mTOR axis. These findings elucidate the mechanistic role of SerpinB1a in HPS progression and suggest its potential as a novel therapeutic target for HPS.