From metabolic antagonism to homeostatic restoration: rewiring hepatic stellate cell bioenergetics for liver fibrosis reversal

Abstract

Emerging evidence has redefined metabolic reprogramming in hepatic stellate cells (HSCs) from a mere energy-supporting process to an active driver of liver fibrosis. Unlike conventional descriptions that focus on isolated pathway alterations, recent advances show that activated HSCs coordinate a multi-layered metabolic remodeling involving glucose, lipid, and amino acid networks. This review highlights three paradigm-shifting insights. First, glycolytically derived lactate not only serves as a metabolic byproduct but also acts as an epigenetic signal through histone lactylation, Which may contribute to the maintenance of fibrogenic gene expression. Second, metabolic crosstalk—exemplified by GLUT1-containing exosomes released from activated HSCs that reprogram quiescent neighboring cells—has been reported to mediate intercellular propagation of the fibrotic phenotype. Third, HSC activation is characterized by stage-specific metabolic vulnerabilities: early lipophagy supports fatty acid oxidation, whereas fully activated HSCs transition to a unique “dual hypermetabolic” state featuring concurrent glycolysis and tricarboxylic acid cycle engagement. Translational efforts have moved beyond single-pathway inhibition toward restoring metabolic homeostasis, with clinical-stage agents such as EVT0185 (a dual ACLY/ACSS2 inhibitor), VDR agonists, and ROCK2 inhibitors showing early promise. We propose that future anti-fibrotic strategies should prioritize stage-specific metabolic signatures, dynamic metabolomics-guided trial design, and the development of highly selective metabolic modulators that reverse, rather than merely block, HSCs activation. A metabolism-centric approach may provide a promising therapeutic direction for the management of chronic liver disease.