Lysine lactylation-mediated post-translational modification: Molecular mechanisms and therapeutic target exploration...

Tumour drug resistance remains a major hurdle in cancer treatment, with post-translational modifications (PTMs) playing a pivotal role in this process. Lysine lactylation (Kla), a newly identified PTM, is tightly associated with the Warburg effect, where tumour cells favour glycolysis even under aerobic conditions, resulting in excessive lactate accumulation. As a key substrate for Kla, this surplus lactate leads to markedly elevated Kla levels in tumours.

This review systematically outlines the molecular mechanisms of Kla, including its biochemical definition, enzymatic regulation, metabolic cross-talk and feedback mechanisms within tumour reprogramming. Furthermore, we comprehensively discuss how Kla promotes tumour drug resistance through diverse mechanisms: activating DNA damage repair pathways, mediating epigenetic regulation and gene expression reprogramming, remodelling the tumour microenvironment (TME) to facilitate immune evasion and disrupting the balance between cell survival and apoptosis. Additionally, we analyse Kla's context-specific characteristics and mechanisms in drug resistance across distinct cancer types, such as breast, colorectal, lung and pancreatic cancer. Notably, we further expand the discussion to the spatial and clonal heterogeneity of Kla within the same tumour, including the divergent Kla profiles between hypoxic tumour cores and oxygen-rich tumour peripheries, the distinct Kla status of circulating tumour cells compared with primary tumour sites, and the specific Kla signatures that distinguish drug-resistant clones from drug-sensitive counterparts, key biological features that are critical for understanding Kla-driven drug resistance but have been largely understudied. Finally, we explore potential Kla-targeted therapeutic strategies, including inhibition of key lactate-metabolising enzymes, modulation of lactyltransferase activity and combination therapies, while discussing current challenges and future directions.

By unravelling these Kla-driven mechanisms, this review provides a novel metabolic-epigenetic axis for overcoming cancer therapeutic resistance. Kla serves as a metabolic-epigenetic switch governed by writer-eraser-reader regulatory systems, directly connecting the Warburg effect to diverse forms of tumour drug resistance. Pharmacological modulation of Kla offers an innovative precision therapeutic approach to reverse drug resistance and enhance clinical prognosis across various malignancies.

Lysine lactylation (Kla) functions as a metabolic-epigenetic switch that directly links the Warburg effect to tumour drug resistance via the writer-eraser-reader regulatory framework Kla promotes drug resistance through four interconnected mechanisms: DNA damage repair activation, epigenetic reprogramming, immune microenvironment remodelling, and anti-apoptotic pathway engagement. Intratumoural Kla exhibits profound spatial and clonal heterogeneity, with distinct Kla profiles in hypoxic tumour cores, oxygen-rich peripheries, circulating tumour cells, and drug-resistant clones. Kla-targeted therapeutic strategies-including inhibition of lactate-metabolising enzymes, modulation of lactyltransferase/delactylase activity, and combination therapies-offer a novel precision approach to reverse drug resistance.