Autophagy in ischemic stroke: pathophysiology, therapeutics, and challenges ahead.

Authors

Tshibambe N Tshimbombu, Arsene Daniel Nyalundja, Gates Mulume Iragi, Josué Aganze Mwambali, Samira Braimah Shardow, Melissa Ewurakua Amoako, Kyle E Thurmann, Daniel I Gonzalez, Paige Banyas, Judea Wiggins, Supreet Kaur

Published in

Frontiers in stroke. Volume 5. Pages 1769395. Epub Jul 20, 2026.

Abstract

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.

PMID:
42548587
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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