HSD17B13 liquid-liquid phase separation promotes liver inflammation in metabolic dysfunction-associated steatohepatitis 2316

Description A protein-truncating variant of 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) has been found to reduce the progression from steatosis to steatohepatitis. Here, we discovered that HSD17B13 forms liquid-liquid phase separation (LLPS) around lipid droplets in the livers of metabolic dysfunction-associated steatohepatitis (MASH) patients. The dimerization of HSD17B13 supports the formation of LLPS and enhances its enzymatic function. HSD17B13 LLPS increases the biosynthesis of platelet-activating factor (PAF), which in turn promotes fibrinogen synthesis and leukocyte adhesion. Importantly, adeno-associated viral-mediated xeno-expression of human HSD17B13 exacerbated western diet/carbon tetrachloride-induced liver inflammation in Hsd17b13-/- mice. In conclusion, our results suggest that HSD17B13 LLPS triggers liver inflammation by promoting PAF-mediated leukocyte adhesion, and targeting HSD17B13 phase transition could be a promising therapeutic approach for treating hepatic inflammation in chronic liver disease. Funding Sources Supported by National Natural Science Foundation of China (81874317, 82273989, 81722047); Fundamental Research Fund of the State Key Laboratory of Pharmaceutical Biotechnology (LNSN-202403).