Context-dependent effects of 6-gingerol on ferroptosis and pyroptosis in disease and therapeutics

Introduction Apoptosis resistance in cancer and chronic inflammatory diseases has driven interest in alternative regulated cell death pathways. Ferroptosis and pyroptosis are distinct yet interconnected mechanisms with important pathophysiological roles. 6-gingerol ([6]-jiang fen ), the bioactive phenolic constituent of Zingiber officinale ( Sheng jiang ), traditionally used in TCM to warm the middle Jiao , dispel cold, and reduce inflammation, exerts pleiotropic, context- and dose-dependent effects via Nrf2/Keap1, PI3K/AKT/mTOR, NLRP3, and MAPK signaling, positioning it as a multi-target therapeutic candidate. Methods A structured narrative review with a systematic search was conducted in PubMed, Scopus, and Google Scholar from inception to April 2026. Of 385 records, 157 duplicates were removed, 228 titles/abstracts screened, and 38 full texts assessed, yielding 13 core studies directly investigating 6-gingerol effects on ferroptosis and/or pyroptosis. These were quality-appraised and supplemented by mechanistic literature on signaling, crosstalk, and disease biology. Results 6-Gingerol shows context-dependent activity, inducing ferroptosis and immunogenic cell death in cancer cells via USP14/NCOA4-mediated ferritinophagy, Fe²⁺-driven lipid peroxidation, and HMGB1/calreticulin/ATP release. In non-malignant tissues, it generally suppresses ferroptosis and pyroptosis through Nrf2-associated antioxidant and anti-inflammatory mechanisms, restoring GPX4/SLC7A11, normalising iron homeostasis, and inhibiting NLRP3. Seven of thirteen core studies included mechanistic validation, and eight combined in vitro/in vivo evidence. Discussion 6-Gingerol's dual regulatory pharmacology offers a rational framework for targeting ferroptosis and pyroptosis in oncological and inflammatory conditions. However, current evidence remains preclinical, and clinical translation requires bioavailability-enhanced formulations, rigorous PK-PD characterisation, and well-designed human trials.