{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T21:58:36Z","timestamp":1776549516766,"version":"3.51.2"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Oxidative stress is a central driver of brain aging, impairing cellular function and increasing susceptibility to neurodegenerative diseases. Recent studies suggest that the RNA demethylase FTO regulates N6-methyladenosine (m6A) RNA modification, a key pathway in modulating oxidative stress in the brain. However, the precise mechanisms underlying FTO\u2019s role remain unclear. This study examines the neuroprotective potential of MO-I-500, a small-molecule FTO inhibitor, against oxidative stress induced by tert-butyl hydroperoxide (TBHP) in neuron-like SH-SY5Y cells differentiated with retinoic acid and BDNF (dSH-SY5Y).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>dSH-SY5Y cells were treated with MO-I-500 alone for 72 h or with TBHP alone for 24 h. Alternatively, cells were pretreated with 1 \u03bcM MO-I-500 for 48 h, followed by co-treatment with MO-I-500 and 25 or 50 \u03bcM TBHP for an additional 24 h, for a total treatment duration of 72 h. Cellular metabolism was assessed using a Seahorse XF MitoStress assay, and oxidative stress markers, including ROS and superoxide levels, were quantified with DCFDA and MitoSOX probes. ATP content was measured using a bioluminescence assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FTO inhibition by MO-I-500 induced a metabolic shift toward an energy-efficient state, enhancing cellular resilience to oxidative stress. Pretreatment significantly reduced TBHP-induced oxidative damage, lowering intracellular ROS levels and preserving ATP content.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Together with our previous findings demonstrating the protective effects of MO-I-500 in astrocytes and recent studies supporting the importance of astrocyte function in neurodegeneration, these results suggest a dual protective role of MO-I-500 in neurons and astrocytes. This dual action positions MO-I-500 as a promising therapeutic strategy to mitigate oxidative damage and reduce the risk of neurodegenerative diseases, including Alzheimer\u2019s disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnmol.2025.1736173","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:13:11Z","timestamp":1768205591000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Small molecule FTO inhibitor MO-I-500 protects differentiated SH-SY5Y neuronal cells from oxidative stress"],"prefix":"10.3389","volume":"18","author":[{"given":"Denise","family":"Greco","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuzana","family":"\u010co\u010dkov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debanjan","family":"Das","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akash S.","family":"Mali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u0159\u00ed","family":"Novotn\u00fd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark J.","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"Telensk\u00fd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1089\/ARS.2012.4615","article-title":"P53 orchestrates the PGC-1\u03b1-mediated antioxidant response upon mild redox and metabolic imbalance","volume":"18","author":"Aquilano","year":"2013","journal-title":"Antioxid. 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