Dual Regulation of ACSL3 by TRIM33-Mediated Ubiquitination and NBR1-Dependent Autophagy: A Therapeutic Target for Cerebral Ischemia-Reperfusion Injury
TL;DR
A novel autophagy–NBR1/TRIM33/TRIM33–ACSL3 regulatory axis that drives ferroptosis in CIRI is revealed, highlighting a promising therapeutic strategy for ischemic stroke through cotargeting autophagy and ferroptosis.
Abstract
Background: Cerebral ischemia-reperfusion injury (CIRI) is a key contributor to stroke-related neurological damage, but the functional interplay between autophagy and ferroptosis—two critical pathological processes—remains poorly understood. Methods: Using oxygen-glucose deprivation/reperfusion in PC12 cells and middle cerebral artery occlusion (MCAO) in rats, we combined molecular, pharmacological, and imaging approaches to investigate how autophagy regulates the ferroptosis suppressor acyl-CoA synthetase long-chain family member 3 (ACSL3). Results: Ischemia-reperfusion triggered hyperactivated autophagy, which promoted ferroptosis by selectively targeting ACSL3 for degradation via the autophagy receptor neighbor of BRCA1 gene 1 protein (NBR1). We further identified that tripartite motif-containing protein 33 (TRIM33), an E3 ubiquitin ligase induced after ischemia, directly ubiquitinates ACSL3 and facilitates its proteasomal degradation. This ubiquitin-mediated pathway acted synergistically with autophagy to control ACSL3 stability. Pharmacological inhibition of autophagy with curcumin derivative 5g (CUR5g) restored ACSL3 protein levels and suppressed ferroptosis. In MCAO rats, CUR5g—administered alone or in combination with the ferroptosis inhibitor Ferfluor-1—significantly improved functional recovery and reduced brain injury. Conclusion: Our study reveals a novel autophagy–NBR1/TRIM33–ACSL3 regulatory axis that drives ferroptosis in CIRI, highlighting a promising therapeutic strategy for ischemic stroke through cotargeting autophagy and ferroptosis. Antioxid. Redox Signal. 45, 676–692.