{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:51:19Z","timestamp":1785919879113,"version":"3.56.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Spinocerebellar ataxia type 3 (SCA3), also known as Machado\u2013Joseph disease, is an autosomal dominant polyglutamine neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3). Mutant ataxin-3 accumulation, oxidative stress, mitochondrial dysfunction, and impaired protein quality control contribute to its pathogenesis; however, no disease-modifying therapy is currently available. Omaveloxolone (RTA-408), an activator of nuclear factor erythroid 2\u2013related factor 2 (Nrf2), is approved for Friedreich\u2019s ataxia, but its therapeutic potential in SCA3 remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the effects of RTA-408 in MJD78 cells and Drosophila SCA3 models. Cell viability, apoptosis, mutant ataxin-3 levels, Nrf2-associated antioxidant proteins, p62\/autophagy-related markers, and mitochondrial phenotypes were assessed in MJD78 cells. Survival, climbing ability, and external eye degeneration were evaluated in SCA3tr-Q78 flies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In MJD78 cells, 0.3 and 0.5 \u03bcM RTA-408 more consistently improved cell viability, reduced apoptosis, and decreased detectable mutant ataxin-3 accumulation than 0.1 \u03bcM RTA-408. RTA-408 increased the nuclear-to-cytoplasmic Nrf2 ratio and upregulated NQO1, HO-1, and SOD2 without significantly altering intracellular or mitochondrial reactive oxygen species levels. RTA-408 also increased p62 expression, whereas ATG7, Beclin 1, LAMP2, and the LC3-II\/LC3-I ratio showed limited or nonsignificant changes, indicating p62 upregulation without definitive evidence of canonical autophagic flux activation. In addition, 0.3 \u03bcM RTA-408 partially shifted mitochondrial morphology from globe-like to elongated forms and increased mitochondrial DNA copy number. In SCA3tr-Q78 flies, RTA-408 partially improved survival, locomotor performance, eye size, and pigmentation, with more evident benefits at earlier stages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support the protective potential of RTA-408 in SCA3-related models. Its effects were associated with activation of Nrf2-related antioxidant responses, p62 upregulation, and selected improvements in mitochondrial phenotypes. Further studies are needed to clarify the underlying mechanisms and determine the translational potential of RTA-408 for SCA3.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1872142","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:32:37Z","timestamp":1785918757000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic potential of the Nrf2 activator omaveloxolone in spinocerebellar ataxia type 3 in cellular and Drosophila models"],"prefix":"10.3389","volume":"17","author":[{"given":"Shin-Hung","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Vascular and Genomic Center, Institute of ATP, Changhua Christian Hospital","place":["Changhua, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jui-Chih","family":"Chang","sequence":"additional","affiliation":[{"name":"Center of Regenerative Medicine and Tissue Repair, Institute of ATP, Changhua Christian Hospital","place":["Changhua, Taiwan"]},{"name":"General Research Laboratory of Research Department, Changhua Christian Hospital","place":["Changhua, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Hsuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Vascular and Genomic Center, Institute of ATP, Changhua Christian Hospital","place":["Changhua, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Hsin","family":"Leng","sequence":"additional","affiliation":[{"name":"Department of Vascular and Genomic Center, Institute of ATP, Changhua Christian Hospital","place":["Changhua, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Ling","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Vascular and Genomic Center, Institute of ATP, Changhua Christian Hospital","place":["Changhua, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Yong","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Chinese Medicine, Graduate Institute of Integrated Medicine, China Medical University","place":["Taichung, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-San","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Vascular and Genomic Center, Institute of ATP, Changhua Christian Hospital","place":["Changhua, Taiwan"]},{"name":"Department of Neurology, Changhua Christian Hospital","place":["Changhua, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6532","DOI":"10.1074\/jbc.M109.036335","article-title":"Nuclear aggregation of polyglutamine-expanded ataxin-3: fragments escape the cytoplasmic quality control","volume":"285","author":"Breuer","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3195","DOI":"10.1093\/hmg\/ddg344","article-title":"The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity","volume":"12","author":"Burnett","year":"2003","journal-title":"Hum. Molecular Genetics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"649","DOI":"10.3390\/antiox13060649","article-title":"The role of NRF2 in trinucleotide repeat expansion disorders","volume":"13","author":"Chang","year":"2024","journal-title":"Antioxidants"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e01414","DOI":"10.1002\/brb3.1414","article-title":"Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population","volume":"9","author":"Chen","year":"2019","journal-title":"Brain Behavior"},{"key":"B5","volume-title":"FDA Approves First Treatment for Friedreich\u2019s Ataxia","year":"2023"},{"key":"B6","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1093\/hmg\/ddi472","article-title":"Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3","volume":"15","author":"Haacke","year":"2006","journal-title":"Hum. Molecular Genetics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"5933","DOI":"10.3390\/ijms23115933","article-title":"Mitochondrial dysfunction in spinocerebellar ataxia type 3 is linked to VDAC1 deubiquitination","volume":"23","author":"Harmuth","year":"2022","journal-title":"Int. Journal Molecular Sciences"},{"key":"B8","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1002\/ana.25934","article-title":"Safety and efficacy of omaveloxolone in friedreich ataxia (MOXIe study)","volume":"89","author":"Lynch","year":"2021","journal-title":"Ann. Neurology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"104635","DOI":"10.1016\/j.nbd.2019.104635","article-title":"Pathogenesis of SCA3 and implications for other polyglutamine diseases","volume":"134","author":"McLoughlin","year":"2020","journal-title":"Neurobiol. Disease"},{"key":"B10","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1093\/brain\/awp292","article-title":"Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3","volume":"133","author":"Menzies","year":"2010","journal-title":"Brain"},{"key":"B11","doi-asserted-by":"publisher","first-page":"7405","DOI":"10.3390\/ijms24087405","article-title":"Autophagy in spinocerebellar ataxia type 3: from pathogenesis to therapeutics","volume":"24","author":"Paulino","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e1002212","DOI":"10.1371\/journal.pcbi.1002212","article-title":"Automatic morphological subtyping reveals new roles of caspases in mitochondrial dynamics","volume":"7","author":"Peng","year":"2011","journal-title":"PLoS Computational Biology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1073\/pnas.0709336105","article-title":"The PINK1\/Parkin pathway regulates mitochondrial morphology","volume":"105","author":"Poole","year":"2008","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/0012-1606(88)90139-x","article-title":"The locus elav of Drosophila melanogaster is expressed in neurons at all developmental stages","volume":"126","author":"Robinow","year":"1988","journal-title":"Dev. Biology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1074\/jbc.M114.590281","article-title":"p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies","volume":"290","author":"Saitoh","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1001087","DOI":"10.1371\/journal.pgen.1001087","article-title":"Inhibition of GSK-3 ameliorates A\u03b2 pathology in an adult-onset drosophila model of alzheimer's disease","volume":"6","author":"Sofola","year":"2010","journal-title":"PLoS Genetics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1007\/s00415-018-9076-4","article-title":"Spinocerebellar ataxia: an update","volume":"266","author":"Sullivan","year":"2019","journal-title":"J. Neurology"},{"key":"B18","volume-title":"A Language and Environment for Statistical Computing","author":"Team","year":"2025"},{"key":"B19","doi-asserted-by":"publisher","first-page":"120111","DOI":"10.1016\/j.lfs.2021.120111","article-title":"Nrf2\/Keap1\/ARE signaling: towards specific regulation","volume":"291","author":"Ulasov","year":"2022","journal-title":"Life Sciences"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2689","DOI":"10.1093\/hmg\/11.22.2689","article-title":"Aggregate formation inhibits proteasomal degradation of polyglutamine proteins","volume":"11","author":"Verhoef","year":"2002","journal-title":"Hum. Molecular Genetics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/s0092-8674(00)81200-3","article-title":"Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in drosophila","volume":"93","author":"Warrick","year":"1998","journal-title":"Cell."},{"key":"B22","doi-asserted-by":"publisher","first-page":"893","DOI":"10.3390\/cells12060893","article-title":"Autophagy function and benefits of autophagy induction in models of spinocerebellar ataxia type 3","volume":"12","author":"Watchon","year":"2023","journal-title":"Cells"},{"key":"B23","doi-asserted-by":"publisher","first-page":"26436","DOI":"10.1074\/jbc.M803692200","article-title":"The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains","volume":"283","author":"Winborn","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"11641","DOI":"10.1038\/s41598-017-11839-0","article-title":"Treatment with caffeic acid and resveratrol alleviates oxidative stress induced neurotoxicity in cell and drosophila models of spinocerebellar ataxia type3","volume":"7","author":"Wu","year":"2017","journal-title":"Sci. Reports"},{"key":"B25","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.freeradbiomed.2017.12.011","article-title":"Caffeic acid and resveratrol ameliorate cellular damage in cell and drosophila models of spinocerebellar ataxia type 3 through upregulation of Nrf2 pathway","volume":"115","author":"Wu","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.3390\/antiox11071389","article-title":"In vitro efficacy and molecular mechanism of curcumin analog in pathological regulation of spinocerebellar ataxia type 3","volume":"11","author":"Wu","year":"2022","journal-title":"Antioxidants"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.3390\/antiox13121495","article-title":"Erinacine A-enriched Hericium erinaceus mycelium ethanol extract lessens cellular damage in cell and drosophila models of spinocerebellar ataxia type 3 by improvement of Nrf2 activation","volume":"13","author":"Wu","year":"2024","journal-title":"Antioxidants"},{"key":"B28","doi-asserted-by":"publisher","first-page":"14997","DOI":"10.3390\/ijms150914997","article-title":"p62\/sequestosome 1 regulates aggresome formation of pathogenic ataxin-3 with expanded polyglutamine","volume":"15","author":"Zhou","year":"2014","journal-title":"Int. Journal Molecular Sciences"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1872142\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:32:38Z","timestamp":1785918758000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1872142\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":28,"alternative-id":["10.3389\/fphar.2026.1872142"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1872142","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"article-number":"1872142"}}