Crotonylation: A novel layer of the epigenetic landscape in disease

Abstract

Crotonylation is a lysine acylation modification that links cellular metabolism to epigenetic regulation. Its rigid planar crotonyl group is specifically recognized by "readers" such as YEATS/DPF and confers strong conformational regulatory capacity on proteins. Crotonyl-CoA, derived from amino acid catabolism, fatty acid β-oxidation, and gut microbial metabolites, directly modulates crotonylation levels, positioning this modification as a key metabolite sensor. Crotonylation extensively modifies both histones and non-histone proteins, participating in transcription, DNA repair, autophagy, ferroptosis, and metabolic regulation. Dynamic crosstalk with SUMOylation, ubiquitination, and acetylation forms regulatory switches that control genome stability and disease progression. In cancer, crotonylation drives metabolic reprogramming, radio-/chemoresistance, remodeling of the tumor microenvironment, and immune evasion, making it a key and vulnerable therapeutic target. Emerging evidence highlights the involvement of crotonylation in modulating immunotherapy responses and ferroptosis, further expanding its therapeutic relevance. Recent advances in chemical biology and deep learning-such as covalent binders, SiTomics photo-crosslinking probes, and predictive models (e.g., nhKcr, Adapt-Kcr)-enable precise detection and functional interrogation of crotonylation in living cells and clinical samples. Crotonylation marks in clinical specimens show potential as diagnostic and prognostic biomarkers. This review highlights these emerging concepts and discusses the therapeutic potential of targeting crotonylation "writers", "erasers", and "readers" for future precision medicine.

Keywords: Cancer; Crotonylation; Histone modification; Metabolic reprogramming; Short-chain acylation.