Ranganathan, VeenaDeepashree, Vidyaranyapura S.Gowda, JadeppaDey, Sumit K.Manjunath, Souparnika H.Anantharaju, Preethi G.Bidye, Durgesh PareshPujar, Gurubasavaraj V.Maharaj, Vinesh J.Thimmulappa, Rajesh K.2025-04-102025-04Ranganathan, V., Deepashree, V.S., Gowda, J. et al. 2025, 'Piper betle extract inhibits ferroptosis by scavenging oxyradicals, hydroperoxides and inducing NRF2 regulated antioxidants', Food Bioscience, vol. 66, art. 106325, pp. 1-15, doi : 10.1016/j.fbio.2025.106325.2212-4292 (print)2212-4306 (online)10.1016/j.fbio.2025.106325http://hdl.handle.net/2263/101992DATA AVAILABILITY : Data will be made available on request.Ferroptosis, an iron catalysed programmed cell death initiated by membrane lipid peroxidation (LPO), is implicated in various degenerative diseases. We screened medicinal/food plants and discovered leaf extract of Piper betle (PB), a popular mouth freshener, as a ferroptosis inhibitor. Compared to vehicle, PB suppressed LPO and inhibited ferroptosis triggered by rotenone or RSL3. Mechanistic studies revealed that PB extract is a powerful lipophilic radical trapping antioxidant and an inducer of Nuclear factor-erythroid 2-Related Factor 2 (NRF2) regulated antioxidant defenses (glutathione/glutathione peroxidase-4 axis). Utilizing diverse free radical systems (hydroxyl, peroxyl, hydroperoxides) and LPO models (serum, LDL), we found that PB extract effectively inhibits LPO by scavenging lipid oxyradicals. LC-HRMS analysis identified hydroxychavicol and polyphenols as the key bioactive constituents in PB extract. In a Drosophila model of rotenone-induced neurotoxicity, PB extract supplementation prevented locomotor deficits and mortality compared to the control diet. In conclusion, PB extract could be developed as a nutraceutical for mitigating ferroptosis-linked disorders.en© 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies. Notice : this is the author’s version of a work that was accepted for publication in Food Bioscience. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. A definitive version was subsequently published in Food Bioscience, vol. 66, art. 106325, pp. 1-15, 2025, doi : 10.1016/j.fbio.2025.106325.Piper betleFerroptosisOxyradicalsLipid hydroperoxidesNeurotoxicityLipid peroxidation (LPO)Nuclear factor-erythroid 2-related factor 2 (NRF2)SDG-03: Good health and well-beingPostprint Article