{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:24:56Z","timestamp":1787635496181,"version":"build-2736575974"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"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. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cerebral ischemia\/reperfusion (I\/R) injury severely limits the efficacy of recanalization therapy for ischemic stroke. Activin A (Act A), a neurotrophic cytokine, shows protective potential, but its mechanisms related to mitochondrial biogenesis and ferroptosis regulation remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vivo<\/jats:italic>\n                      , adult male Wistar rats (12\/group) underwent 2\u202fh middle cerebral artery occlusion (MCAO) and 24\u202fh reperfusion. Act A (7.5\u202f\u03bcg\/kg) or vehicle was administered intracerebroventricularly pre-ischemia. TTC, TEM, and IHC were used to analyze cerebral I\/R injury and PGC-1\u03b1 expression.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , HT22 cells exposed to oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R, 8\u202fh\/24\u202fh) were treated with Act A (100\u202fng\/mL). Ferroptosis markers, mitochondrial function and signaling pathways were assessed via qPCR, western blot, flow cytometry, laser confocal and ChIP.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vivo<\/jats:italic>\n                      , Act A significantly reduced cerebral infarct volume versus vehicle (***\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001), decreased MDA levels (***\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001), and increased PGC-1\u03b1 expression (***\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001) along with mtDNA copy number (*\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05).\n                      <jats:italic>In vitro<\/jats:italic>\n                      , Act A rescued OGD\/R-induced ferroptosis, suppressing lipid ROS (**\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.01) and Fe\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation (*\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05). It activated the PGC-1\u03b1\/NRF1\/TFAM axis (*\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05) and enhanced mitochondrial biogenesis. Mechanistically, Act A promoted PGC-1\u03b1 transcription via Smad3 binding to its promoter (*\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05) and enhanced PGC-1\u03b1 activity through p38-MAPK phosphorylation (***\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001). Silencing PGC-1\u03b1 abolished Act A\u2019s neuroprotection effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Act A mitigates cerebral I\/R injury by dual activation of PGC-1\u03b1 through Smad3 and p38-MAPK pathways, enhancing mitochondrial biogenesis and inhibiting neuronal ferroptosis. This highlights Act A as a therapeutic candidate for ischemic stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1842829","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:41:54Z","timestamp":1781239314000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Activin A mitigates ferroptosis in cerebral ischemia\/reperfusion injury via the PGC-1\u03b1\/NRF1\/TFAM axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiahui","family":"Yang","sequence":"first","affiliation":[{"name":"China-Japan Union Hospital, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Shi","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Ma","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Liu","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Cui","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongxin","family":"Xu","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaoqi","family":"Wang","sequence":"additional","affiliation":[{"name":"China-Japan Union Hospital, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e036142","DOI":"10.1161\/JAHA.124.036142","article-title":"Projections of the stroke burden at the global, regional, and National Levels up to 2050 based on the global burden of disease study 2021","volume":"13","author":"Cheng","year":"2024","journal-title":"J Am Heart Assoc"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1056\/NEJMoa2413344","article-title":"Alteplase for posterior circulation ischemic stroke at 4.5 to 24 hours","volume":"392","author":"Yan","year":"2025","journal-title":"N Engl J 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