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Activin receptor\u2010interacting protein 1 (ARIP1) is a negative regulator of the activin signaling pathway in neurons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study investigated whether activin A inhibits neuronal ferroptosis and the role of ARIP1 in cerebral ischemic injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      In this study, activin A increased the viability of primary neurons under conditions of oxygen\u2013glucose deprivation (OGD). Subsequent RNA\u2010sequencing analysis of activin A\u2010treated neurons identified expression of\n                      <jats:italic>Slc7a11<\/jats:italic>\n                      as the ferroptosis\u2010associated gene with significant upregulation. Next, using the CRISPR\/Cas9 system, mice were generated with a heterozygous deficiency of ARIP1 (\n                      <jats:italic>Arip1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/+<\/jats:italic>\n                      <\/jats:sup>\n                      ), and the results revealed that the expression of GPX4 was markedly elevated and SLC7A11 was reduced in OGD\u2010treated\n                      <jats:italic>Arip1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/+<\/jats:italic>\n                      <\/jats:sup>\n                      neurons, compared with that in wild\u2010type (WT) neurons, which was accompanied by an increase of p\u2010SMAD3 and a decrease of p\u2010p38 MAPK levels. In addition, our data showed that activin A activated SMAD3 and inhibited p38 MAPK phosphorylation, which differentially modulated SLC7A11 and GPX4 expression, ultimately suppressing OGD\u2010induced ferroptosis. Notably,\n                      <jats:italic>Arip1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/+<\/jats:italic>\n                      <\/jats:sup>\n                      mice showed an improvement in neurological deficits and reduced cerebral infarction in the permanent middle cerebral artery occlusion (pMCAO) model. Furthermore, we observed that activin A exerted similar protective effects against ischemic injury in\n                      <jats:italic>Arip1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/+<\/jats:italic>\n                      <\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings indicate that downregulating the expression of ARIP1 suppresses neuronal ferroptosis by modulating SLC7A11\/GPX4 expression via SMAD3 and p38 MAPK signaling, ultimately enhancing the neuroprotective role of activin A against cerebral ischemia.<\/jats:p>\n                  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