Crotonate enhances intestinal regeneration after injury via HBO1-mediated H3K14 crotonylation.

The intestinal epithelium undergoes rapid turnover driven by Lgr5(+) intestinal stem cells at the crypt base, and can recover upon damage. Histone crotonylation plays a critical role in chromatin regulation and gene expression. However, the role of histone crotonylation, specifically H3K14 crotonylation (H3K14cr) in the intestine remains poorly understood. Here we demonstrate that both crotonate and H3K14cr levels are increased in the regenerating crypts. Treatment with sodium crotonate significantly alleviates dextran sulfate sodium induced colitis, an effect largely dependent on HBO1-mediated H3K14cr. Notably, HBO1 deficiency severely dampens regeneration, correlating with reduced H3K14ac and H3K14cr levels, decreased chromatin accessibility at transcriptional start sites, and impaired expression of stem and fetal genes. Single-cell RNA sequencing analysis reveals that HBO1 is expressed in stem cells and regenerative cells during recovery after irradiation, further supporting the critical role of HBO1 in intestinal regeneration. Together, our findings uncover a mechanism by which crotonate, HBO1, and H3K14cr contribute to epithelial regeneration and suggest that crotonate may represent a promising therapeutic agent for the treatment of gastrointestinal diseases.