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This study identified significantly elevated plasma RCAN1.1 levels in acute ischemic stroke (AIS) patients and demonstrated that mitochondrial translocation of RCAN1.1L \u200cwithin the ischemic penumbra\u200c aggravates cerebral infarction \u200cby promoting pathological mitochondrial fission and neuronal apoptosis\u200c. Mechanistically, in AIS cell and mouse models, multi-omics screening identified\n                    <jats:italic>activating transcription factor 2<\/jats:italic>\n                    (\n                    <jats:italic>ATF2<\/jats:italic>\n                    ) mRNA as a critical downstream target of RCAN1.1L. RCAN1.1L binds to the 2915-2935 nucleotide in the 3\u2019-untranslated region (UTR) of\n                    <jats:italic>ATF2<\/jats:italic>\n                    mRNA, stabilizing its expression and promoting the accumulation of mitochondrial ATF2 (mtATF2) protein. MtATF2, in turn, binds to and upregulates mitochondrial fission 1 (FIS1) protein, thereby enhancing mitochondrial fission and driving intrinsic apoptosis. Notably, the RNA aptamer R1SR13 competitively binds to RCAN1.1L protein with\n                    <jats:italic>ATF2<\/jats:italic>\n                    mRNA, exerting neuroprotective effects by disrupting the RCAN1.1L-mtATF2-FIS1 axis. These findings identify RCAN1.1L as an upstream regulator of\n                    <jats:italic>ATF2<\/jats:italic>\n                    mRNA stability-mediated mitochondrial fission and apoptosis in ischemic penumbra neurons and highlight R1SR13 as a promising therapeutic candidate for preserving neuronal mitochondrial integrity.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08809-8","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T21:27:11Z","timestamp":1778707631000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RNA-binding protein RCAN1.1L modulates ATF2 mRNA stability to promote mitochondrial fission in acute ischemic stroke"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9826-4597","authenticated-orcid":false,"given":"Yanbin","family":"Ji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaxin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexin","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9179-1543","authenticated-orcid":false,"given":"Shuangwu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuchen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dexin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9501-2546","authenticated-orcid":false,"given":"Yuguo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2294-7000","authenticated-orcid":false,"given":"Yan","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8206-1346","authenticated-orcid":false,"given":"Xiulian","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"8809_CR1","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1056\/NEJMcp1917030","volume":"383","author":"WJ Powers","year":"2020","unstructured":"Powers WJ, Solomon CG. 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