Abstract
Spinal cord ischemia-reperfusion injury (SCIRI) is a severe secondary complication of trauma, spinal cord decompression, and thoracoabdominal aortic surgery. Ferroptosis, a regulated cell death pathway characterized by iron-dependent accumulation of lethal reactive oxygen species and lipid peroxidation, has been implicated in various pathological conditions. However, its precise role and molecular mechanisms in SCIRI remain unclear. In this study, we demonstrated that ferroptosis contributes to the pathophysiology of SCIRI. Heme oxygenase 1 (HMOX1) was upregulated in both SCIRI rats and neuronal cells subjected to hypoxia-reoxygenation. Genetic knockdown of HMOX1 in vivo and in vitro markedly attenuated neuronal ferroptosis, improving neurological function, whereas HMOX1 overexpression reproduced characteristic ferroptotic events in vitro. HMOX1 upregulation appeared to stimulate autophagic flux and induce substantial mitophagy, suggesting a potential mechanistic link between HMOX1 and ferroptosis promotion. Mitophagy reduction diminished HMOX1-mediated ferroptosis, whereas mitophagy induction acted synergistically with HMOX1. HMOX1 physically interacted with BNIP3, triggering excessive mitophagy and subsequent ferroptosis. In this study, we establish ferroptosis as a critical contributor to SCIRI pathogenesis and identify HMOX1 as a central regulator of this process. Furthermore, mitophagy-dependent ferroptosis, mediated by the HMOX1-BNIP3 axis, emerges as a promising therapeutic target for SCIRI intervention.