Hepatocellular carcinoma (HCC) persists as a leading cause of cancer-related mortality globally. While targeted therapies, including sorafenib and lenvatinib, serve as standard first-line treatments, their efficacy is frequently compromised by low response rates and the rapid development of resistance, posing a significant clinical challenge. Lactylation (Kla), a metabolism-driven post-translational modification stemming from lactate accumulation, has recently emerged as a pivotal regulator of HCC progression and therapeutic resistance. The extent of lactylation is governed by lactate availability, the dynamic balance between "writer" and "eraser" enzymes, and chromatin accessibility. Functionally, Kla augments HCC malignancy by stimulating cell proliferation, modulating metabolic enzyme activity, promoting angiogenesis, and facilitating the remodeling of an immunosuppressive microenvironment. Mechanistically, it confers resistance to targeted therapy by activating antioxidant pathways, sustaining cancer stemness, and reinforcing metabolic reprogramming. Promising strategies to counteract this resistance involve inhibiting lactate production, targeting lactylation "writers," and combining targeted agents with glycolysis inhibitors. This review delineates the regulatory network of lactylation, and the mechanisms of Kla-mediated drug resistance, as well as discusses potential therapeutic strategies to improve patient outcomes. Targeting the lactylation pathway thus represents a promising approach to reverse resistance and enhance the efficacy of targeted therapy in HCC.
Zhu et al. (Wed,) studied this question.