Role and intervention strategies of metabolic-epigenetic cross-talk in the treatment of drug resistance in colorectal cancer

Colorectal cancer (CRC) continues to be one of the most prevalent gastrointestinal malignancies on a global scale. Despite advancements in targeted therapy and immunotherapy that have enhanced outcomes for certain patients, primary and acquired drug resistance remain significant challenges that impede clinical efficacy. Metabolic reprogramming is widely acknowledged as a fundamental hallmark of cancer, facilitating survival advantages for tumor cells by restructuring glucose, amino acid, and lipid metabolic networks. Critically, this reprogramming directly fosters a drug-tolerant phenotype by modifying the flux of metabolic intermediates. Simultaneously, aberrant epigenetic modifications—including the remodeling of DNA methylation, altered histone acylation, and dysregulated non-coding RNA networks—play an indispensable role in the establishment and maintenance of resistance to targeted therapies in CRC. Notably, metabolic reprogramming and epigenetic remodeling do not function independently. Recent research indicates that cellular metabolites serve as substrates or cofactors for the regulation of epigenetic modifying enzymes. Conversely, alterations in the epigenome feedback to regulate the transcription of metabolic enzymes. This interplay establishes a bidirectional regulatory mechanism.