Regulatory Effects of Plant-Derived Phenolic Compounds on Ferroptosis: A Novel Paradigm in Cancer Therapy
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https://doi.org/10.62482/pmj.53Keywords:
Cancer therapy, ferroptosis, lipid peroxidation, network pharmacology, phenolic compoundsAbstract
Ferroptosis is a recently identified, iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and membrane damage, and it has emerged as a promising therapeutic target in cancer treatment. In recent years, increasing attention has been directed to plant-derived phenolic compounds due to their potent redox-modulating, metal-chelating, and signaling-regulatory properties. This review provides a comprehensive overview of the molecular mechanisms by which phenolic compounds regulate ferroptosis in cancer cells. Phenolics modulate ferroptosis through multiple pathways, including suppression of glutathione peroxidase 4 (GPX4), depletion of intracellular glutathione (GSH), disruption of iron homeostasis via ferritinophagy, and acceleration of lipid peroxidation mediated by acyl-CoA synthetase long-chain family member 4 (ACSL4)- and arachidonate lipoxygenase (ALOX)-dependent pathways. In addition, redox-sensitive signaling axes, particularly the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, play a dual role by conferring cytoprotective effects in normal cells while promoting ferroptosis resistance in tumor cells. Recently, in silico, network pharmacology, and omics-based studies further reveal that phenolic compounds exert their effects via complex multi-target networks rather than single protein inhibition. Moreover, nanotechnological carrier systems significantly improve the bioavailability, tumor selectivity, and ferroptosis-inducing efficacy of phenolic compounds. Collectively, the available preclinical evidence highlights plant-derived phenolics as promising ferroptosis modulators and potential adjuvant agents in cancer therapy. Unlike previous reviews that focus primarily on either ferroptosis signaling or general anticancer effects of polyphenols, this review integrates molecular mechanisms, systems-level analyses, and delivery strategies to present a unified framework for phenolic-driven ferroptosis modulation in cancer.
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