Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the need for innovative therapeutic strategies beyond current chemotherapeutics and immunotherapies. Curcumin, a natural polyphenol derived from Curcuma longa, exhibits pleiotropic anticancer properties; however, its molecular mechanisms of action in CRC remain incompletely defined. This systematic review critically synthesizes evidence from 20 in vitro studies published between 2023 and 2025 to map the molecular actions of curcumin and evaluate its translational potential. Across multiple CRC cell lines, free curcumin inhibited cell proliferation with IC50 values ranging from 10 to 25 µM (HCT116 cells: ~19 µM; SW480: ~15.6 µM; HT29: ~22 µM), while nanoformulations and synthetic analogues enhanced cytotoxic potency by approximately 1.5–4-fold. Mechanistically, curcumin consistently induced apoptosis through upregulation of Bax, downregulation of Bcl-2, activation of caspase-3, and cleavage of PARP. Ferroptosis was mediated by suppression of GPX4 and FSP1, accompanied by reactive oxygen species (ROS) accumulation and lipid peroxidation, and was reversible by ferrostatin-1. Curcumin further modulated key epigenetic regulators, including EZH2, MLL1, and G9a, resulting in stabilization of wild-type p53 and lysosomal degradation of mutant p53, while also inhibiting Wnt/β-catenin signaling and the EGR1–TERT/SIRT6 axis. Genotype-dependent responses were evident, with KRAS-mutant cells undergoing G2/M arrest, HT29 cells (BRAF/TP53-mutant) exhibiting G0/G1 arrest, and LoVo cells displaying features of cellular senescence. Migration and invasion were consistently suppressed, particularly by targeted formulations, while minimal cytotoxicity was observed in non-malignant cells. Collectively, these findings demonstrate that curcumin functions as a multimodal modulator of oncogenic pathways in CRC. Its potential as an adjuvant therapeutic is particularly evident when combined with genotype-stratified strategies and advanced delivery systems, although further studies are required to address dosing constraints and methodological heterogeneity
Esmaeli et al. (Thu,) studied this question.