HSD17B13 Couples Hepatocyte Lipid Metabolism to Stellate Cell Activation via TGFb-1 Signaling

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by hepatocellular lipid overload, immune activation, and hepatic stellate cell (HSC)-driven fibrogenesis. Human genetic studies reveal that loss-of-function (LoF) variants in 17 beta-hydroxysteroid dehydrogenase 13 ( HSD17B13 ) confer robust protection against advanced fibrosis and cirrhosis, establishing HSD17B13 as a critical genetic modifier of MASH severity. Yet the mechanisms linking HSD17B13 activity to fibrogenic progression remain poorly understood. Here, we show that both wild-type and catalytically deficient HSD17B13 (mHSD) localize to lipid droplets (LDs) in cultured human hepatocytes, but only catalytically active HSD17B13 enhances hepatocellular lipid accumulation and markedly upregulates the lipogenic transcriptional regulator carbohydrate-responsive element-binding protein (ChREBP). This HSD17B13-driven lipogenic axis elicits potent paracrine activation of LX2 stellate cells, both in hepatocyte-HSC co-culture and in response to hepatocyte-conditioned medium (CM). Screening of candidate signaling mediators revealed that transforming growth factor beta-1 (TGFb-1) is uniquely and strongly upregulated by active HSD17B13, with minimal induction by mHSD. Remarkably, siRNA-mediated knockdown of TGFB1 or neutralization of active TGFb-1 protein abolishes CM-induced LX2 activation and collagen synthesis. Collectively, these findings identify HSD17B13 as a dual metabolic and profibrotic effector that drives TGFb-1-dependent HSC activation, thereby linking hepatocellular lipid dysregulation to fibrogenic progression and providing a mechanistic framework for understanding how HSD17B13 contributes to MASH pathogenesis.