The Dual Role of Folate Metabolism in Colorectal Cancer: Bridging Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms, Molecular Subtypes and Precision Prevention
Year: 2025
Type: article
Abstract: Colorectal cancer (CRC) exhibits complex heterogeneity driven by the interplay of genetic, metabolic, and microenvironmental factors.Folate metabolism, essential for nucleotide synthesis and epigenetic regulation, paradoxically influences CRC pathogenesis: deficiency increases initiation risk, while excess supplementation may accelerate established tumors.Central to this duality is methylenetetrahydrofolate reductase (MTHFR), whose polymorphisms (e.g., C677T, A1298C) modulate folate flux, altering DNA methylation-nucleotide synthesis balance in a context-dependent manner.Emerging evidence suggests that MTHFR variants interact with Consensus Molecular Subtypes-CMS1 (microsatellite instability), CMS3 (metabolic dysregulation), CMS2/4 (WNT/stromal-driven)-to dictate divergent folate dependencies.For instance, CMS1 tumors may exploit folate for immune evasion via adenosine signaling, whereas CMS2/4 subtypes rely on folate-mediated epigenetic reprogramming.However, current prevention strategies neglect these subtype-specific vulnerabilities, treating CRC as a monolithic entity.This review synthesizes evidence from Mendelian randomization, preclinical models, and subtype-stratified trials to propose three critical advances: (1) Subtype-Driven Folate; (2) Dependency Biomarker Integration; (3) Microenvironment Crosstalk.
Source: Research Review
Author: Yanxi Shen
Institution: Nanjing University of Chinese Medicine
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4409689742