Piperine as a Multifunctional Epigenetic Modulator: Integrative Molecular Insights into Cancer and Chronic Disease Therapy

Piperine, the principal alkaloid of Piper nigrum, has gained attention as a multifunctional dietary compound with broad effects on epigenetic and transcriptional regulation in cancer and chronic diseases. Evidence shows that piperine modulates DNA methylation (↓ DNMT3B), histone acetylation (↓ HDAC activity), and microRNA networks (↑ miR-29c, ↓ miR-383), thereby reshaping key oncogenic and tumor-suppressive pathways. Beyond canonical epigenetic control, it can also stabilize G-quadruplex structures in promoters such as c-MYC, adding an architecture-based mechanism of transcriptional repression. Its dual redox behavior—antioxidant at low doses and pro-oxidant at higher doses—confers context-dependent selectivity, enabling oxidative stress–mediated apoptosis in tumor cells. Compared with other nutriepigenetic agents (curcumin, resveratrol, EGCG), piperine stands out for its multi-target profile and preliminary evidence of activity against cancer stem cell–like phenotypes. Nonetheless, limited solubility, rapid metabolism, and scarce in vivo validation constrain clinical translation. Future efforts should focus on advanced formulations, multi-omics approaches, and cancer stem cell models to better define its therapeutic potential and safety.