{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:02:01Z","timestamp":1784523721833,"version":"3.55.0"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"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. Stroke"],"abstract":"<jats:p>Autophagy is a fundamental cellular homeostatic process that exerts a dual, context-dependent influence on the pathophysiology of ischemic stroke. Functioning as both a neuroprotective survival mechanism and a neurotoxic pathway, autophagy presents a complex therapeutic challenge as well as a potential target for molecular intervention. This narrative review synthesizes preclinical and emerging clinical evidence to summarize key mechanisms regulating autophagy in ischemic injury, evaluate therapeutic strategies, and identify promising molecular pathways and druggable targets for translational development. In the early ischemic phase, moderate autophagic activation facilitates neuronal survival by clearing damaged mitochondria and protein aggregates, thereby reducing oxidative stress and modulating neuroinflammation. This protective response is primarily mediated by regulators such as Beclin-1, the conversion of LC3-I to LC3-II, and the energy-sensing AMP-activated protein kinase pathway. Conversely, sustained or excessive autophagy, particularly during late-stage reperfusion, exacerbates neuronal injury through impaired lysosomal fusion, autophagosome accumulation, and the triggering of autophagic cell death and ferroptosis. Preclinical evidence highlights a critical Goldilocks zone of activation, suggesting that therapeutic success hinges on maintaining autophagic flux within narrow physiological limits. Advancing these therapies into clinical practice requires precise spatiotemporal modulation, potentially as an adjunct to mechanical thrombectomy, as well as the development of robust, real-time biomarkers. A comprehensive understanding of the molecular and genetic determinants of autophagy, including sex-specific responses, is essential to bridge the translational gap and establish autophagy as a viable target for precision stroke medicine.<\/jats:p>","DOI":"10.3389\/fstro.2026.1769395","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:20:41Z","timestamp":1784521241000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Autophagy in ischemic stroke: pathophysiology, therapeutics, and challenges ahead"],"prefix":"10.3389","volume":"5","author":[{"given":"Tshibambe N.","family":"Tshimbombu","sequence":"first","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arsene Daniel","family":"Nyalundja","sequence":"additional","affiliation":[{"name":"Center for Tropical Diseases and Global Health, Faculty of Medicine, Universit\u00e9 Catholique de Bukavu","place":["Bukavu, Democratic Republic of Congo"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gates Mulume","family":"Iragi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universit\u00e9 Catholique de Bukavu","place":["Bukavu, Democratic Republic of Congo"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josu\u00e9 Aganze","family":"Mwambali","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universit\u00e9 Catholique de Bukavu","place":["Bukavu, Democratic Republic of Congo"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira Braimah","family":"Shardow","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Ghana","place":["Accra, Ghana"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Ewurakua","family":"Amoako","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Ghana","place":["Accra, Ghana"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle E.","family":"Thurmann","sequence":"additional","affiliation":[{"name":"School of Medicine, Creighton University","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel I.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Banyas","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judea","family":"Wiggins","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1007\/s10787-024-01606-9","article-title":"Neuroprotective effects of phytochemicals through autophagy modulation in ischemic stroke","volume":"33","author":"Ahmadzadeh","year":"2025","journal-title":"Inflammopharmacology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"107848","DOI":"10.1016\/j.pharmthera.2021.107848","article-title":"Targeting autophagy in ischemic stroke: from molecular mechanisms to clinical therapeutics","volume":"225","author":"Ajoolabady","year":"2021","journal-title":"Pharmacol. 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