Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications Colorectal cancer (CRC) is a prevalent digestive system malignancy, ranking third and second in global incidence and mortality in 2020. It affects 1.93 million people globally, with 940,000 deaths. CRC incidence in younger patients is rising. CRC development is driven by genetic and epigenetic abnormalities in normal colonic epithelial cells and tumor microenvironment changes. While genetic changes are primary drivers, epigenetic regulation plays a crucial role in cancer progression. This review discusses CRC's global epidemiology, risk factors, and prevention strategies. It explores recent advances in epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), which hold potential as screening tools, prognostic biomarkers, and therapeutic targets for CRC. Epigenetics involves genetic architecture and biochemical modifications of chromatin, regulating gene activity without altering DNA sequences. Epigenetic mechanisms, such as DNA methylation, histone modifications, and ncRNA regulation, are involved in gene expression and epigenetic silencing, influencing processes like cell differentiation, gene expression, and genomic imprinting. Epigenetic regulation is a key factor in CRC drug resistance. For example, aberrant expression of the CRC epigenome can lead to resistance against conventional drugs like 5-fluorouracil. Epigenetic changes are prime candidates for cancer detection, diagnosis, and prognosis. Classic CRC biomarkers, such as KRAS and BRAF mutations, NDRG4, BMP3, and SEPT9 methylation, miR-92a and miR-144 expression, and F. nucleatum presence, are used in liquid biopsies for early CRC screening. Epigenetic regulation is reversible with pharmacological interventions. For example, histone H3 lysine residue methylation inhibits EGFR transcription, and treatment with KDM4 inhibitors can decrease EGFR amplification, overcoming drug resistance in advanced CRC. Methylation and deacetylation of histone H3 promote LncRNA-CCAL expression, activating the Wnt/β-catenin pathway and upregulating ABCB1, leading to multidrug resistance in CRC. Understanding epigenetic drivers of CRC and developing specific epigenetic-targeted drugs targeting ncRNAs or reversing histone modifications and DNA methylation holds significant potential for precision medicine in CRC patients. This review provides an overview of CRC's current worldwide epidemiology, risk factors, and prevention strategies. It summarizes common CRC epigenetic modifications, including DNA methylation, histone modifications, and ncRNA regulation. It screens for potential epigenetic biomarkers from previous articles, aiming to improve early screening, diagnosis, prognosis, and targeted drug treatment for CRC, and lay the foundation for future personalized medicine.Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications Colorectal cancer (CRC) is a prevalent digestive system malignancy, ranking third and second in global incidence and mortality in 2020. It affects 1.93 million people globally, with 940,000 deaths. CRC incidence in younger patients is rising. CRC development is driven by genetic and epigenetic abnormalities in normal colonic epithelial cells and tumor microenvironment changes. While genetic changes are primary drivers, epigenetic regulation plays a crucial role in cancer progression. This review discusses CRC's global epidemiology, risk factors, and prevention strategies. It explores recent advances in epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), which hold potential as screening tools, prognostic biomarkers, and therapeutic targets for CRC. Epigenetics involves genetic architecture and biochemical modifications of chromatin, regulating gene activity without altering DNA sequences. Epigenetic mechanisms, such as DNA methylation, histone modifications, and ncRNA regulation, are involved in gene expression and epigenetic silencing, influencing processes like cell differentiation, gene expression, and genomic imprinting. Epigenetic regulation is a key factor in CRC drug resistance. For example, aberrant expression of the CRC epigenome can lead to resistance against conventional drugs like 5-fluorouracil. Epigenetic changes are prime candidates for cancer detection, diagnosis, and prognosis. Classic CRC biomarkers, such as KRAS and BRAF mutations, NDRG4, BMP3, and SEPT9 methylation, miR-92a and miR-144 expression, and F. nucleatum presence, are used in liquid biopsies for early CRC screening. Epigenetic regulation is reversible with pharmacological interventions. For example, histone H3 lysine residue methylation inhibits EGFR transcription, and treatment with KDM4 inhibitors can decrease EGFR amplification, overcoming drug resistance in advanced CRC. Methylation and deacetylation of histone H3 promote LncRNA-CCAL expression, activating the Wnt/β-catenin pathway and upregulating ABCB1, leading to multidrug resistance in CRC. Understanding epigenetic drivers of CRC and developing specific epigenetic-targeted drugs targeting ncRNAs or reversing histone modifications and DNA methylation holds significant potential for precision medicine in CRC patients. This review provides an overview of CRC's current worldwide epidemiology, risk factors, and prevention strategies. It summarizes common CRC epigenetic modifications, including DNA methylation, histone modifications, and ncRNA regulation. It screens for potential epigenetic biomarkers from previous articles, aiming to improve early screening, diagnosis, prognosis, and targeted drug treatment for CRC, and lay the foundation for future personalized medicine.