Abstract Hepatocellular carcinoma (HCC) has high global morbidity and mortality. Advanced HCC depends on systemic therapies, but primary/acquired drug resistance severely limits patient survival, creating an urgent need for new targets. This review focuses on how lactylation modification drives HCC drug resistance. In recent years, lactylation, a novel type of post-translational modification (PTM) of proteins mediated by the metabolic product lactate, has been found to be widely involved in the regulation of malignant progression, maintenance of stem cell characteristics, and treatment resistance in HCC. Lactylation conjugates lactate to histones and non-histones, regulating gene expression. Key resistance pathways include: lactylated IGF2BP3 activating PCK2-NRF2 to counter lenvatinib-induced stress; ALDOA lactylation enhancing liver cancer stem cell self-renewal for chemoresistance; MOESIN lactylation in Regulatory T cells (Tregs) weakening anti-PD-1 efficacy. HCC lactylation levels are higher than normal tissues (correlating with poor prognosis); lactylation-related genes/models predict treatment responses. Therapeutically, 2-DG, AZD3965, or SIRT3 activators (reverse lactylation) restore drug sensitivity, alone or in combination. Despite limited specific detectors, lactylation is a promising target to overcome HCC drug resistance, aiding precision treatment.
Zhu et al. (2026) studied this question.