Berberine-induced ferroptosis as a novel anti-cancer strategy: molecular, epigenetic and translational perspectives

Cancer cells frequently evade therapies that depend on apoptosis, necessitating the exploration of alternative cell death mechanisms. Ferroptosis, an iron-dependent regulated cell death characterized by lethal lipid peroxidation, has emerged as a promising strategy for cancer treatment. Recent studies have identified berberine, an isoquinoline alkaloid derived from Coptis chinensis and Berberis species, as an inducer of ferroptosis in various malignancies through its multitarget effects. This review systematically elucidates the molecular pathways through which berberine induces ferroptosis. These pathways include the inhi bition of the System Xc⁻/glutathione/glutathione peroxidase 4 antioxidant axis, disruption of iron homeostasis via ferritinophagy, inhibition of mitochondrial complex I, and regulation of the upstream regulators p53, nuclear factor erythroid 2-related factor 2, and Gli1/signal transducer and activator of transcription 3 axis. Evidence specific to various cancer types, including nasopharyngeal, lung, colorectal, gastric, hepatocellular, pancreatic, prostate cancer, and osteosarcoma, was critically evaluated. Translational strategies, such as combination therapy, nanodelivery systems, and machine learning-directed structural optimization, have been examined. Additionally, the challenges of low bioavailability, resistance to ferroptosis, and complex immunological responses are discussed. Preclinical evidence suggests that berberine exhibits significant epigenetic activity, including the inhibition of DNA methyltransferases (DNMT1/DNMT3), histone modifications (H3K9me3 via SETDB1, H3K27me3 via EZH2), and modulation of oncogenic/tumor-suppressor microRNAs (e.g., miR-21, miR-155). These actions enhance its ferroptotic effects and may synergistically in crease the sensitivity of cancer cells to lipid peroxidation. Although primarily based on preclinical findings, these epigenetic mechanisms represent a crucial and underexplored aspect of berberine's anticancer potential.