{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T13:08:19Z","timestamp":1770901699896,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Environmental Health Sciences at the National Institutes of Health","award":["ES035019"],"award-info":[{"award-number":["ES035019"]}]},{"name":"National Institute of Environmental Health Sciences at the National Institutes of Health","award":["ES025750"],"award-info":[{"award-number":["ES025750"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Necrox-5 is an indole-derived antioxidant that inhibits necrotic cell death, likely through prevention of mitochondrial stress, oxidative stress, inflammation, and hypoxia\/reoxygenation. However, its protective role against ferroptotic toxicity has not yet been studied. In this study, we induced ferroptosis in HT-22 cells, an immortalized hippocampal neuronal cell line, using ferroptosis-inducing agents. We also tested Necrox-5 against toxicity induced by propargite, a pesticide known to inhibit complex V (mitochondrial adenosine triphosphate [ATP] synthase) and induce necrosis. We evaluated cytotoxicity using calcein AM and lactate dehydrogenase (LDH) release assays. Additionally, we conducted intracellular and cell-free C11-BODIPY assays to assess the efficacy of Necrox-5 in inhibiting lipid peroxidation. Intracellular glutathione (GSH) levels were measured using the mBCI-GSH assay, while ATP levels were determined through bioluminescence assays. Our findings show that Necrox-5 is a potent inhibitor of ferroptosis induced by erastin, RSL3, FINO2, and iron plus arachidonic acid. Furthermore, we demonstrated that Necrox-5 protects against ferroptosis-like propargite toxicity, although it did not prevent propargite-induced depletion of GSH and ATP. We identified radical-scavenging antioxidant activity as the primary mechanism by which Necrox-5 protects from ferroptosis and propargite toxicity. In conclusion, Necrox-5 is a potent cytoprotective compound that warrants further study for its potential role in ferroptosis-associated complications such as neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/ijms27041772","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:05:46Z","timestamp":1770897946000},"page":"1772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytoprotective Mechanism of Necrox-5 Against Toxicity Induced by Experimental Ferroptosis Instigators and the Pesticide Propargite"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8216-1171","authenticated-orcid":false,"given":"Md.","family":"Jakaria","sequence":"first","affiliation":[{"name":"School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason R.","family":"Cannon","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1007\/s12272-010-1114-4","article-title":"NecroX as a novel class of mitochondrial reactive oxygen species and ONOO(-) scavenger","volume":"33","author":"Kim","year":"2010","journal-title":"Arch. 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