Curcumol Induces Necroptosis of Hepatic Stellate Cells by Targeting KAT8 to Suppress HK2 Lactylation and Promote HUWE1-Dependent Ubiquitination

Liver fibrosis is a pathological outcome of chronic liver injury and is primarily driven by the continuous activation of hepatic stellate cells (HSCs). During activation, HSCs depend on aerobic glycolysis to maintain their fibrogenic characteristics, suggesting that metabolic reprogramming could serve as an effective therapeutic approach. In this study, we demonstrate that Curcumol, a natural compound derived from plants in the Zingiberaceae family, selectively removes activated HSCs by interfering with the lactate-KAT8-HK2 regulatory pathway. In HSCs, lactate produced through glycolysis activates the acetyltransferase KAT8, which catalyzes K346 lactylation of hexokinase 2 (HK2). This modification creates a positive feedback mechanism that stabilizes HK2. Curcumol acts directly on KAT8, inhibiting HK2 lactylation and promoting HUWE1-mediated ubiquitination and degradation of HK2. The resulting loss of HK2 removes its inhibitory influence on RIPK1 ubiquitination, leading to activation of the RIPK1/RIPK3/MLKL signaling pathway and triggering necroptosis. <i>In vivo</i> experiments show that Curcumol substantially reduces liver fibrosis, lowers the expression of glycolytic enzymes, and improves liver function in mice with carbon tetrachloride (CCl₄)-induced fibrosis. However, these protective effects are lost when KAT8 is overexpressed. This study highlights HK2 lactylation as a key metabolic control point for HSC survival and identifies Curcumol as a potential anti-fibrotic compound that targets the KAT8-HK2 pathway, linking metabolic inhibition with necroptotic cell death.