Dendrobium Officinale Polysaccharide Inhibits Ferroptosis and Ameliorates Cerebral Ischemia–Reperfusion Injury: Involvement of the Nrf2/GPX4 Signaling Pathway

Abstract Ferroptosis, a critical pathological mechanism in ischemic stroke (IS), is activated during the early phase of cerebral ischemia–reperfusion injury (CI/RI). Dendrobium officinale polysaccharide (DOP), the primary bioactive component of Dendrobium officinale , exhibits diverse pharmacological activities, including antioxidant, anti-inflammatory, and immunomodulatory effects. DOP has been suggested to exert neuroprotective effects by inhibiting ferroptosis; however, its specific role and underlying mechanisms in IS-related ferroptosis remain unclear. In this study, in vivo and in vitro CI/RI models were established using middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen–glucose deprivation/reoxygenation (OGD/R), respectively. DOP was administered under a paradigm combining long-term pretreatment and short-term post-ischemic intervention, and its neuroprotective effects were evaluated. In MCAO/R mice, DOP significantly alleviated neurological deficits, reduced the cerebral infarct volume, and mitigated neuronal damage. These effects were associated with decreased Fe 2 ⁺ accumulation and lipid peroxidation, ameliorated mitochondrial impairment, and upregulated the expression of key ferroptosis-related proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4). Consistent with in vivo findings, DOP enhanced the viability of HT-22 cells subjected to OGD/R, decreased reactive oxygen species, and restored the mitochondrial membrane potential, accompanied by increased Nrf2 and GPX4 expression. Notably, knockdown of Nrf2 attenuated GPX4 expression and diminished the protective effects of DOP. Collectively, these findings suggest that DOP exerts neuroprotective effects against CI/RI, at least in part, by inhibiting ferroptosis through the Nrf2/GPX4 signaling pathway, supporting its potential role in preventive and early-stage intervention strategies for ischemic stroke.