Downregulation of COX-2 expression in liver sinusoidal endothelial cell prevented the formation of liver sinusoidal microthrombi through the AKT/mTOR/TSP-1 axis.
Qian Shuaijie S, Gan Can C, Zhao Chong C, Dai Wenting W et al.
Liver sinusoidal microthrombosis (LST) is recognized as an initiating event in fibrogenesis and portal hypertension in chronic liver diseases. Liver sinusoidal endothelial cell (LSEC)-derived chemoattractants recruit neutrophils and macrophages, promoting LST in congestive hepatopathy (CH). However, the driving molecules from LSECs for LST remain unclear. This study aims to elucidate that LSECs inflammatory via cyclooxygenase-2 (COX-2) upregulation triggers metabolic reprogramming promoting thrombospondin-1 (TSP-1)-mediated LST and portal hypertension. A murine model of LST and portal hypertension was established by partial inferior vena cava ligation (pIVCL). LST and portal hypertension were suppressed in both LSEC-specific COX-2 knockout mice (Ptgs2ΔLSEC) and celecoxib-treated wild-type mice induced by pIVCL. RNA sequencing of mouse liver tissue and untargeted metabolomics of human hepatic sinusoidal endothelial cells (HHSECs) revealed that COX-2 inhibition was concurrent with downregulation of the AKT/mTOR pathway, reduced lactate, and decreased TSP-1. In vitro, COX-2-derived prostaglandin E2 (PGE2) activated the AKT/mTOR pathway, driving glycolytic reprogramming and lactate production. In turn, the accumulation of lactate induced by COX-2 upregulation enhanced histone H3K9 lactylation, which transcriptionally upregulated Thbs1 (encoding TSP-1), thereby instigating a prothrombotic phenotype in LSECs. Collectively, this study uncovers a novel pathogenic axis in LST formation, where COX-2 drives a prothrombotic switch in LSECs via AKT/mTOR-mediated metabolic reprogramming and lactate-dependent epigenetic upregulation of TSP-1. Targeting LSEC COX-2 may represent a promising therapeutic strategy for mitigating LST and portal hypertension.