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

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.