Beyond a Metabolite: Lactylation as a Pivotal Regulator of Colorectal Cancer Pathogenesis and Treatment Resistance

Abstract

Colorectal cancer (CRC) is a highly lethal malignancy worldwide. Lactylation, which serves as a key metabolic‐epigenetic bridge driving malignant progression, is involved in CRC development, metastasis, immunosuppression, and drug resistance. This review systematically outlines the biological functions of lactate and the molecular mechanisms of lactylation, with a particular focus on their regulatory roles in CRC. Key aspects are summarized, including the dynamic regulation by lactylation‐related enzymes (“writers” and “erasers”) and potential therapeutic strategies targeting lactylation. Distinct from existing studies, this review further explores the clinical translational potential of targeting lactylation. From a toxicological perspective, it analyzes mechanisms of chemotherapy resistance and the toxicological considerations associated with targeted therapies. Core challenges in clinical translation, such as off‐target toxicity, optimization of the therapeutic index, and low drug delivery efficiency—are also examined. By synthesizing the latest research advances in lactylation modification in CRC, this review provides a clear framework to inform and guide subsequent basic research and clinical translation efforts.