FiLactate‐Induced Lysine Lactylation: A Central Node Linking Metabolic Rewiring, Epigenetic Plasticity and Therapeutic Vulnerabilities in Hepatocellular Carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) exploits aerobic glycolysis to generate a surplus of lactate that fuels malignant growth, immune evasion, and drug resistance. Lysine lactylation (Kla), deposited by p300/CBP using lactyl‐CoA and removed by sirtuin deacylases, has emerged as a pivotal conduit through which lactate rewires chromatin architecture and protein function. Following PRISMA‐compliant screening of 612 publications, 45 high‐quality studies published between 2019 and 2025 were integrated with our own multi‐omics interrogation of 1,128 tumours. Histone H3/H4 Kla amplifies glycolytic, epithelial‐to‐mesenchymal transition, and multidrug‐resistance programmes, forging a feed‐forward metabolic‐epigenetic circuit. Non‐histone Kla targeting ALDOA^K230/322, c‐Myc, YAP, and STAT3 stabilises oncogenic signalling, sustains PI3K–AKT–mTOR and Wnt/β‐catenin cascades, and preserves liver cancer stem‐cell self‐renewal. Concomitantly, Kla skews tumour‐associated macrophages toward an M2 phenotype, activates cancer‐associated fibroblasts and endothelial cells, and suppresses cytotoxic lymphocyte infiltration, collectively sculpting an immunosuppressive niche. A Kla‐high transcriptional signature shortens median overall survival by 18 months and stratifies patients with poor response to sorafenib and immune checkpoint blockade. Three convergent therapeutic entry points emerge: depletion of lactate via glycolytic inhibition or MCT1/4 blockade (FX11, AZD3965), enzymatic modulation of Kla writers or erasers, and PROTAC‐mediated degradation of oncogenic lactylated proteins. In murine and patient‐derived xenograft models, these strategies reduce tumour volume by at least 50% and synergise durably with anti‐PD‐1 therapy. This integrated synthesis positions lysine lactylation as a hierarchical regulator that links metabolic stress to epigenetic plasticity, immune escape, and therapeutic vulnerability, and outlines a biomarker‐driven roadmap for lactylation‐targeted precision medicine in HCC.