This comprehensive review aims to systematically clarify how the newly identified post-translational modification—lysine lactylation—reprograms hepatocellular carcinoma (HCC) biology and to evaluate its potential as both a predictive biomarker and a druggable vulnerability. By integrating the most recent in-vitro, in-vivo and clinical proteomic data, we delineate three core messages. First, lactate is no longer a mere waste product of the Warburg effect: it is a central signaling metabolite that accumulates up to ten-fold in HCC tissue, fuels an acidic micro-environment, and supplies the substrate for widespread protein lactylation. Second, lactylation operates through both enzyme-dependent (“writer” p300/GCN5/HBO1, “eraser” HDAC1-3/Sirtuins, “reader” Brg1) and enzyme-independent (methylglyoxal-derived lactoyl-glutathione) mechanisms, thereby modulating chromatin accessibility, transcription-factor stability, metabolic-enzyme activity and sub-cellular protein trafficking. Consequently, hyper-lactylation accelerates every hallmark of HCC aggressiveness—G1/S transition (H3K9/56la, CCNE2-K348la), anabolic rewiring (SCD1, AK2, LDHA feedback loops), epithelial–mesenchymal transition (TPX2, PKM2, Rab7A lactylation) and immune escape (PD-L1, NUPR1, MOESIN lactylation)—while also fostering stemness and resistance to lenvatinib, cisplatin and microwave ablation. Third, because lactylation levels correlate tightly with tumour grade, micro-vascular invasion and overall survival, site-specific lactylation signatures (H3K18la, AK2-K28la, CENPA-K124la, USP14-K336la, ABCF1-K430la) can complement classical AFP and imaging-based surveillance. Therapeutically, we propose a “lactylation clamp” strategy: combine (i) lactate-lowering agents (LDH inhibitors such as FX11, MCT1/4 blockers such as AZD3965, HK2 silencers), (ii) selective p300 catalytic inhibitors (e.g., C646 derivatives) to dampen writing, and (iii) SIRT3 agonists or CRISPR-based HDAC1-3 over-expression to enhance erasing, while monitoring target inhibition with quantitative lactyl-proteomics. Importantly, disruption of the lactylation axis re-sensitizes HCC to PD-1 checkpoint blockade, suggesting that lactylation-directed therapy can be synergistic rather than competitive with immunotherapy. Given the safety record of metabolic modulators in humans, we advocate rapid translation of these combinations into neoadjuvant or adjuvant clinical trials, with H3K18la and AK2-K28la as pharmacodynamic end-points. Aiming to dissect the impact of lactate and lactylation on hepatocellular carcinoma, this review seeks to furnish novel methodologies and conceptual frameworks for predicting tumour progression, evaluating therapeutic efficacy, and tailoring individualized treatment strategies for HCC patients.
Wu et al. (Thu,) studied this question.