Emerging histone post-translational modifications in colorectal cancer progression: Mechanisms, immune modulation, and therapeutic implications

Colorectal cancer (CRC) ranks among the most common and lethal cancers worldwide, and its incidence has increased markedly among younger populations.Patients with advanced CRC generally have a poor prognosis, mainly due to metastasis and therapeutic resistance.Recently, emerging histone post-translational modifications (HPTMs) -including lactylation, crotonylation, citrullination, succinylation, propionylation, and monoaminylation -have attracted considerable attention as important epigenetic regulatory mechanisms.These modifications link metabolic alterations with transcriptional regulation and may therefore play critical roles in tumor initiation and progression.This review summarizes the regulatory mechanisms of these six HPTMs and evaluates the accumulating evidence connecting them with CRC pathogenesis.Particular emphasis is placed on the context-dependent functions of these modifications during CRC progression and the complex crosstalk among different HPTMs.We also discuss recent advances in analytical technologies that enable genome-wide profiling and unbiased identification of these low-abundance modifications.Direct therapeutic approaches targeting these HPTMs in CRC remain at an early stage.Nevertheless, several smallmolecule inhibitors targeting related regulatory enzymes have demonstrated preclinical potential to inhibit tumor progression and alleviate therapeutic resistance in CRC cell lines and animal models.However, most available evidence is derived from preclinical studies, and the clinical relevance of these findings requires further validation in patient cohorts and well-designed clinical trials.Overall, this review provides an integrated overview of emerging HPTMs in CRC and may serve as a valuable reference for future mechanistic investigations and clinical translation.These efforts may ultimately facilitate the development of combination therapeutic strategies incorporating epigenetic agents for CRC treatment.