Electroacupuncture Alleviates Cerebral Ischemia-Reperfusion Injury by Modulating Autophagy-Ferroptosis via STAT3/HIF-1α Pathway

Focal cerebral ischemia-reperfusion injury (CIRI) remains a significant challenge in stroke management, often leading to severe neuronal damage exacerbated by oxidative stress and neuroinflammation. Current therapeutic strategies often fall short in fully mitigating the complex cellular cascades involved. Electroacupuncture (EA) has shown promise in neuroprotection, but its precise mechanisms, particularly regarding the intricate crosstalk between autophagy and ferroptosis, have been largely unexplored. Understanding how EA influences these critical cell death pathways could unlock novel adjunctive therapies for stroke patients.

Researchers investigated electroacupuncture's neuroprotective effects using both in vivo and in vitro models. In vivo, MCAO/R mice were subjected to middle cerebral artery occlusion/reperfusion to simulate CIRI, followed by EA intervention. Therapeutic efficacy was assessed via behavioral tests, cerebral blood flow measurement, and cerebral infarction volume analysis. In vitro, oxygen-glucose deprivation/reperfusion (OGD/R) was applied to neuronal cells. Molecular analyses, including immunofluorescence staining, western blot analysis, and transmission electron microscopy, were used to examine the STAT3/HIF-1α pathway activity and its relationship with autophagy and ferroptosis markers.

In MCAO/R mice, electroacupuncture intervention significantly improved neurological functional recovery, decreased cerebral infarction volume, and enhanced cerebral blood flow. Molecularly, EA was found to downregulate the activation of the STAT3/HIF-1α signalling pathway. Furthermore, EA treatment was associated with reduced markers of excessive autophagy and diminished ferroptosis markers in neurons, indicating a protective effect against these cell death mechanisms. The study also revealed a critical role for STAT3 activation: > IL-6-mediated enhancement of STAT3 phosphorylation significantly weakened EA's protective effects against cerebral ischemia-reperfusion injury, highlighting STAT3 as a key regulatory node. In vitro experiments further supported this, as STAT3 knockdown prevented OGD/R-induced activation of STAT3/HIF-1α signalling, which was accompanied by reduced autophagy and ferroptosis markers, reinforcing the pathway's involvement in EA's neuroprotective actions.