Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (4): 1652-1664.doi: 10.4103/NRR.NRR-D-24-00674

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Voltage-dependent anion channel 1 oligomerization regulates PANoptosis in retinal ischemia–reperfusion injury

Hao Wan1 , Xiaoxia Ban1 , Ye He1 , Yandi Yang1 , Ximin Hu1 , Lei Shang2 , Xinxing Wan3 , Qi Zhang1, 4, 5, *, Kun Xiong1, 5, 6, *   

  1. 1 Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China;  2 Jiangxi Research Institute of Ophthalmology and Visual Sciences, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi Province, China;  3 Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China;  4 Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, USA;  5 Key Laboratory of Emergency and Trauma of Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, Hainan Province, China;  6 Hunan Key Laboratory of Ophthalmology, Changsha, Hunan Province, China
  • Online:2026-04-15 Published:2025-07-28
  • Contact: Kun Xiong, MD, PhD, xiongkun2001@163.com; Qi Zhang, PhD, zhangqi2014@csu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82172196 (to KX), 82372507 (to KX); the Natural Science Foundation of Hunan Province, China, No. 2023JJ40804 (to QZ); and the Key Laboratory of Emergency and Trauma (Hainan Medical University) of the Ministry of Education, China, No. KLET-202210 (to QZ).

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Abstract: Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration. PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis, apoptosis, and necroptosis. Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury. However, its role in PANoptosis remains largely unknown. In this study, we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury. Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury. Mechanistically, mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly. Moreover, inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury. Overall, our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury, highlighting voltage-dependent anion channel 1 as a promising therapeutic target.

Key words: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, apoptosis, ischemia–reperfusion injury, mitochondrial dysfunction, necroptosis, oxidative stress, PANoptosis, pyroptosis, reactive oxygen species, voltage-dependent anion channel 1