{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:09:24Z","timestamp":1788768564028,"version":"build-2803163510"},"reference-count":91,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>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\u2014exemplified by GLUT1-containing exosomes released from activated HSCs that reprogram quiescent neighboring cells\u2014has 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 \u201cdual hypermetabolic\u201d 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.<\/jats:p>","DOI":"10.3389\/fmed.2026.1912158","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T07:37:55Z","timestamp":1788766675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From metabolic antagonism to homeostatic restoration: rewiring hepatic stellate cell bioenergetics for liver fibrosis reversal"],"prefix":"10.3389","volume":"13","author":[{"given":"Xinyu","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First 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