PANoptosis and Mitochondrial Regulatory Mechanisms in Cerebral Ischemia-Reperfusion Injury

Li Li¹Chunyan Guo¹Zheng Zuo²Luoyang Cai²Xin Chen²Yongjiang Fang¹Shengnan Zhang²Tianyu Chen²Peng Kuang³Zhang Pengyue²Li LI¹Zuhong Wang^1*

• ¹The Third Affiliated Hospital of Yunnan University of Chinese Medicine, Kunming, China
• ²Yunnan University of Chinese Medicine, Kunming, China
• ³Yunnan Cancer Hospital, Kunming, China

Cerebral ischemia-reperfusion injury remains a leading cause of mortality and disability despite advances in reperfusion therapy. Traditional research has focused on individual cell death pathways, yet pharmacological blockade of single pathways provides only partial neuroprotection, suggesting that dying cells engage multiple death routes simultaneously. This review examines whether PANoptosis, an inflammatory cell death modality characterized by concurrent activation of apoptotic, necroptotic, and pyroptotic pathways, occurs in cerebral ischemia-reperfusion injury. The analysis demonstrates that mitochondrial dysfunction serves as the central convergence point orchestrating multi-pathway death activation across distinct temporal phases. Ischemia creates metabolic crisis that primes mitochondria without triggering irreversible commitment. Reperfusion causes explosive mitochondrial collapse through oxidative stress, releasing danger signals that simultaneously engage multiple death pathways. Impaired mitochondrial quality control then sustains inflammatory amplification over extended periods. Multiple lines of evidence support this framework, including concurrent rather than sequential appearance of pathway markers, mixed morphological features within individual cells, pathway redundancy demonstrated by incomplete single-target protection, and mechanistic convergence at the mitochondrial level. Cellular responses vary among neurons, astrocytes, microglia, and endothelial cells but share the common feature of coordinated multi-pathway activation. This integrated understanding explains why single-pathway therapeutic approaches have failed clinically and suggests that effective neuroprotection requires targeting upstream mitochondrial dysfunction or addressing pathway redundancy through multi-target interventions.