{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T10:46:40Z","timestamp":1782470800055,"version":"3.54.5"},"reference-count":67,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cPathogen readiness platform for CERIC\u2013ERIC Upgrade\u201d","award":["IR0000028"],"award-info":[{"award-number":["IR0000028"]}]},{"name":"PRP@CERIC CUP","award":["J97G22000400006"],"award-info":[{"award-number":["J97G22000400006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Ferroptosis has emerged as a critical mechanism linking iron dysregulation, oxidative stress, and neurodegeneration in amyloid-associated pathologies. Building on our previous work, which identified compound 20 as a promising antioxidant and neuroprotective agent, the present study investigates the molecular mechanisms underlying its protective activity against amyloid-induced ferroptosis in human neuroblastoma SH-SY5Y cells exposed to A\u03b2(25\u201335). Compound 20 (3-(((4-hydroxybenzyl)(methyl)amino)methyl)-1-methyl-N-(2-(piperazin-1-yl)ethyl)-1H-indole-5-carboxamide) markedly counteracted A\u03b2(25\u201335)-induced ferroptotic damage by restoring intracellular glutathione levels, depleting the labile iron pool, and suppressing lipid peroxidation. In parallel, the compound significantly rescued mitochondrial membrane potential and attenuated endoplasmic reticulum (ER) expansion associated with ER stress, thereby preserving cellular homeostasis under oxidative challenge. These protective effects were further corroborated by real-time PCR analysis, which revealed the modulation of key genes involved in the oxidative stress response, endoplasmic reticulum stress, and inflammatory pathways. To gain a systems-level insight into these mechanisms, untargeted 1H-NMR metabolomic profiling was performed. This analysis confirmed the activation of antioxidant pathways and disclosed a significant modulation of energy metabolism and GABA-related pathways, both of which are closely linked to redox balance and neuronal resilience. Overall, these findings demonstrate that compound 20 drives metabolic reprogramming that orchestrates its multifactorial protective effect against A\u03b2(25\u201335)-induced ferroptosis by coordinating antioxidant defense, iron homeostasis, and ER stress mitigation.<\/jats:p>","DOI":"10.3390\/antiox15070798","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T08:43:57Z","timestamp":1782463437000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Reprogramming Associated with Ferroptosis Protection by an Indole-Based Antioxidant in A\u03b2(25\u201335)-Treated SH-SY5Y Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6471-5246","authenticated-orcid":false,"given":"Mariapia","family":"Vietri","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8610-879X","authenticated-orcid":false,"given":"Enza","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8296-1888","authenticated-orcid":false,"given":"Maria Rosaria","family":"Miranda","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Marino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8312-4241","authenticated-orcid":false,"given":"Simona","family":"Musella","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1397-5240","authenticated-orcid":false,"given":"Veronica","family":"Di Sarno","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3715-8680","authenticated-orcid":false,"given":"Carmine","family":"Ostacolo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3320-972X","authenticated-orcid":false,"given":"Michele","family":"Manfra","sequence":"additional","affiliation":[{"name":"Department of Health Science, University of Basilicata, Viale dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1069-2181","authenticated-orcid":false,"given":"Pietro","family":"Campiglia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2355-6047","authenticated-orcid":false,"given":"Mario Felice","family":"Tecce","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"D\u2019Ursi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0526-2152","authenticated-orcid":false,"given":"Ornella","family":"Moltedo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Bertamino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via G. 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