Roles of protein crotonylation in tumors: regulatory mechanisms and therapeutic potential

Lysine crotonylation(Kcr), an important protein post-translational modification, establishes a connection between cellular metabolism and epigenetic regulation. This modification utilizes crotonyl-CoA as a donor and is co-regulated by “writers”, “erasers” and “readers”. Furthermore, it participates in key biological processes including gene transcription, metabolic reprogramming, DNA damage repair, and remodeling of the tumor immune microenvironment. Recent studies have demonstrated that crotonylation is dysregulated in various malignant tumors, including breast cancer, colorectal cancer, liver cancer, lung cancer, and glioma. It drives tumor proliferation, invasion, metastasis, and drug resistance by influencing metabolic enzyme activity, chromatin status, DNA repair efficiency, and immune signaling pathways. Lysine crotonylation demonstrates significant environmental-dependence across different cancers; Not only can it promote the malignant phenotype of tumor cells, but it can also potentiate the response to immunotherapy under specific metabolic conditions. Preclinical studies have explored therapeutic strategies targeting tumor crotonylation, including metabolic interventions, enzymatic regulation, and combination immunotherapy; however, these approaches remain investigational and have not been clinically validated. This narrative review summarizes the molecular mechanisms, biological functions, and current advances of crotonylation in diverse malignancies, and highlights unresolved questions and emerging therapeutic hypotheses.