Exogenous hydrogen sulfide alleviates cerebral ischemia/reperfusion injury via inhibiting RIPK1-mediated neuronal necroptosis and ROS overaccumulation.
5 affiliations
- 1Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China.
- 2Department of Neurosurgery, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
- 3Nanchang University, Nanchang, China.
- 4Department of Neurosurgery, The Second Affiliated Hospital of Shandong First Medical University, Taian, China.
- 5Department of Cadre Ward, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, China.
Abstract
Background
Cerebral I/R injury is a significant pathological factor contributing to neuronal death and neurological dysfunction following stroke. Necroptosis and excessive oxidative stress are pivotal mechanisms that drive ischemic neuronal damage. H₂S has been identified as a neuroprotective gaseous signaling molecule; however, its regulatory role in neuronal necroptosis during cerebral I/R injury remains inadequately understood.Methods
In vitro, we established a cell OGD model to simulate neuronal I/R injury. Following pretreatment with NaHS or Necrostatin-1, we assessed cell viability, the necroptotic rate, intracellular ROS levels, mitochondrial membrane potential, and the expression of necroptosis-related proteins. In vivo, we established a mouse model of MCAO/R. After NaHS and Nec-1 intervention, we evaluated neurological deficit scores, cerebral blood perfusion, brain water content, cerebral infarct volume, neuronal ultrastructure, and the expression of RIPKs proteins.Results
OGD treatment resulted in a time-dependent decline in SH-SY5Y cell viability, a significant increase in the rate of neuronal necroptosis, excessive accumulation of ROS, mitochondrial dysfunction, and elevated expression levels of RIPKs and MLKL. Pretreatment with moderate doses of NaHS significantly enhanced cell viability, mitigated ROS overproduction, restored mitochondrial membrane potential, and inhibited OGD-induced neuronal necroptosis. Both NaHS and Nec-1 effectively suppressed the activation of the RIPK1 mediated signaling pathway. In vivo, MCAO/R induced severe neurological dysfunction, cerebral hypoperfusion, brain edema, extensive cerebral infarction, and neuronal ultrastructural damage. NaHS or Nec-1 treatment significantly improved neurological deficits, restored regional cerebral blood flow, reduced brain edema and infarct volume, and alleviated neuronal morphological damage by downregulating the expression of RIPK1 and RIPK3.Conclusion
Necroptosis played a crucial role in acute cerebral I/R injury, both in vitro and in vivo, mediated by RIPK1. Exogenous H₂S or Nec-1 exhibited significant neuroprotective effects against cerebral I/R injury by suppressing RIPK1-mediated neuronal necroptosis and inhibiting ROS. These findings provided a novel theoretical basis for the clinical management of ischemic stroke.
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BibTeX
@article{huang2026exogenous,
title = {{Exogenous hydrogen sulfide alleviates cerebral ischemia/reperfusion injury via inhibiting RIPK1-mediated neuronal necroptosis and ROS overaccumulation.}},
author = {Chuanjiang Huang and Hao Shang and Zhihao Fang and Lei Zhu and Chao Chen and Yanan Zang},
journal = {Frontiers in molecular biosciences},
year = {2026},
month = oct,
doi = {10.3389/fmolb.2026.1968646},
url = {https://europepmc.org/article/MED/42952556},
note = {CC BY},
}
RIS
TY - JOUR
TI - Exogenous hydrogen sulfide alleviates cerebral ischemia/reperfusion injury via inhibiting RIPK1-mediated neuronal necroptosis and ROS overaccumulation.
AU - Chuanjiang Huang
AU - Hao Shang
AU - Zhihao Fang
AU - Lei Zhu
AU - Chao Chen
AU - Yanan Zang
PY - 2026
DA - 2026/10/14
JO - Frontiers in molecular biosciences
DO - 10.3389/fmolb.2026.1968646
UR - https://europepmc.org/article/MED/42952556
AB - Background Cerebral I/R injury is a significant pathological factor contributing to neuronal death and neurological dysfunction following stroke. Necroptosis and excessive oxidative stress are pivotal mechanisms that drive ischemic neuronal damage. H₂S has been identified as a neuroprotective gaseous signaling molecule; however, its regulatory role in neuronal necroptosis during cerebral I/R injury remains inadequately understood.Methods In vitro, we established a cell OGD model to simulate neuronal I/R injury. Following pretreatment with NaHS or Necrostatin-1, we assessed cell viability, the necroptotic rate, intracellular ROS levels, mitochondrial membrane potential, and the expression of necroptosis-related proteins. In vivo, we established a mouse model of MCAO/R. After NaHS and Nec-1 intervention, we evaluated neurological deficit scores, cerebral blood perfusion, brain water content, cerebral infarct volume, neuronal ultrastructure, and the expression of RIPKs proteins.Results OGD treatment resulted in a time-dependent decline in SH-SY5Y cell viability, a significant increase in the rate of neuronal necroptosis, excessive accumulation of ROS, mitochondrial dysfunction, and elevated expression levels of RIPKs and MLKL. Pretreatment with moderate doses of NaHS significantly enhanced cell viability, mitigated ROS overproduction, restored mitochondrial membrane potential, and inhibited OGD-induced neuronal necroptosis. Both NaHS and Nec-1 effectively suppressed the activation of the RIPK1 mediated signaling pathway. In vivo, MCAO/R induced severe neurological dysfunction, cerebral hypoperfusion, brain edema, extensive cerebral infarction, and neuronal ultrastructural damage. NaHS or Nec-1 treatment significantly improved neurological deficits, restored regional cerebral blood flow, reduced brain edema and infarct volume, and alleviated neuronal morphological damage by downregulating the expression of RIPK1 and RIPK3.Conclusion Necroptosis played a crucial role in acute cerebral I/R injury, both in vitro and in vivo, mediated by RIPK1. Exogenous H₂S or Nec-1 exhibited significant neuroprotective effects against cerebral I/R injury by suppressing RIPK1-mediated neuronal necroptosis and inhibiting ROS. These findings provided a novel theoretical basis for the clinical management of ischemic stroke.
SN - 2296-889X
ER -