Protein crotonylation in cancer: mechanisms, functions, and therapeutic potential

Lysine crotonylation (Kcr) has recently emerged as a distinctive post-translational modification with unique structural features and regulatory functions. Since its discovery in 2011, more than 10,000 histone and non-histone crotonylation sites have been identified, underscoring its widespread presence and evolutionary conservation. Crotonylation is dynamically regulated by "writers", "erasers", and "readers", linking metabolic state to chromatin regulation and protein activity. Increasing evidence indicates that dysregulated crotonylation contributes to tumor initiation, progression, metastasis, and therapy resistance across diverse cancer types. Mechanistically, crotonylation modulates gene expression, metabolic reprogramming, DNA repair, and stress responses by modifying both histones and key non-histone proteins. Advances in proteomic technologies have enabled systematic mapping of crotonylomes, facilitating the identification of novel diagnostic biomarkers and therapeutic targets. Here, we summarize current knowledge of the regulatory mechanisms and biological functions of protein crotonylation in cancer, highlight its roles across major tumor types, and discuss emerging opportunities for therapeutic intervention. A deeper understanding of crotonylation biology is expected to expand the epigenetic and metabolic landscape of cancer research and foster the development of precision oncology strategies.