Sinusoidal endothelial cells orchestrate liver inflammation and lipid metabolism via USP12/CD36 axis being the target of celastrol therapy.

Abstract

Disordered lipid metabolism and inflammation, the hallmark features of metabolic dysfunction-associated steatohepatitis (MASH), present a significant therapeutic challenge even in the absence of obesity, making the discovery of novel pathogenic mechanisms and therapies imperative. Although Celastrol (Cel) markedly ameliorates high-fat diet (HFD)-induced obesity, whether and by what molecular basis it directly ameliorates hepatic inflammation and disordered lipid metabolism remains unclear. Here, using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced MASH model, we demonstrate that Cel ameliorates steatohepatitis and identify CD36 in liver sinusoidal endothelial cells (LSECs)-the key gatekeepers of hepatic immunometabolic homeostasis-as the central mediator coordinating hepatic lipid transport and inflammatory responses. Elucidating the regulatory mechanism, we found that USP12 removes K48-linked ubiquitination from CD36 and stabilizes it in LSECs. Cel downregulates USP12, thereby promoting CD36 ubiquitination and subsequent degradation, which in turn attenuates chemokine-driven macrophage recruitment and suppresses pathological lipid transport. The clinical relevance of this axis is supported by the concurrent upregulation of both USP12 and CD36 in human livers with steatohepatitis. These findings reveal that LSEC heterogeneity orchestrates hepatic metabolism and inflammation via the USP12/CD36 axis, designating it a therapeutic target for interventions with agents such as Cel.