Dietary sulforaphane in cancer chemoprevention: epigenetic regulation and PRMT5-MEP50 complex inhibition-a systematic review.

Background: Cancer chemoprevention using dietary bioactive compounds has emerged as a promising, cost-effective strategy to reduce global cancer incidence and mortality. Sulforaphane (SFN), an isothiocyanate abundant in cruciferous vegetables, has attracted considerable attention for its pleiotropic anticancer effects. Methods: This systematic review synthesizes evidence through February 2026, with a particular focus on SFN's roles in epigenetic remodeling and modulating the PRMT5-MEP50 complex. Following PRISMA 2020 guidelines and a PROSPERO-registered protocol (Registration ID: CRD420261435174), we identified 118 eligible studies (17 clinical trials, 31 observational studies, and 70 preclinical mechanistic investigations). Study quality was assessed using Cochrane RoB 2.0, the Newcastle-Ottawa Scale, and SYRCLE's risk-of-bias tool. Results: Recent clinical evidence includes a randomized Phase II trial in high-risk former smokers, in which 12-month supplementation with SFN (95 μmol/day) reduced the bronchial Ki-67 proliferation index by 20%. Meanwhile, the placebo group showed a 65% increase. Across clinical studies, SFN and SFN-rich preparations were well tolerated and associated with favorable changes in proliferation markers, histone acetylation, and tumor suppressor gene expression. Mechanistically, SFN modulates epigenetic networks by inhibiting DNA methyltransferases and histone deacetylases, activating TET-mediated DNA demethylation, and regulating microRNAs and long non-coding RNAs. In parallel, converging preclinical data indicate that SFN targets the oncogenic PRMT5-MEP50 complex through four complementary mechanisms: (1) proteasome-dependent degradation of PRMT5 and MEP50; (2) reduction of PRMT5-MEP50 complex formation; (3) inhibition of histone and non-histone arginine methylation activity; and (4) modulation of PRMT5 subcellular localization, with selective attenuation of cytoplasmic oncogenic functions. Computational molecular docking and cellular co-immunoprecipitation (Co-IP) support the hypothesis that SFN interferes with PRMT5-MEP50 protein-protein interactions (PPIs). Nevertheless, label-free biophysical assays (surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR)) using purified holocomplexes are still lacking to validate direct high-affinity binding between SFN and PRMT5-MEP50. Together, these actions suggest an "epigenetic-PRMT5 inhibition" dual-axis framework that cooperatively reactivates silenced tumor suppressor programs and restricts oncogenic signaling. Conclusion: We discuss key translational issues, including bioavailability limitations, inter-individual variability driven by GST genotypes and gut microbiota, and design considerations for genotype-guided Phase III chemoprevention trials. SFN appears to exemplify a dietary phytochemical with mechanism-based selectivity for cancer cells at nutritional concentrations, an excellent safety profile, and emerging biomarker evidence from randomized trials. If ongoing formulation and precision prevention strategies validate current findings in large-scale trials, SFN may inform the development of safe, accessible, and mechanism-guided cancer chemopreventive interventions. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420261435174.