ABSTRACT Cerebral ischemia/reperfusion injury (CIRI) remains a major clinical challenge due to the lack of effective neuroprotective strategies. Here, hUMSC‐derived exosomes (H‐Exo) were isolated and administered intranasally (15 µg/mouse/day for 3 days) in a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model. Animals were randomly assigned to three groups: Sham, MCAO/R, and H‐Exo–treated MCAO/R mice. H‐Exo efficiently penetrated the blood–brain barrier, accumulated within the ischemic penumbra, and was internalized by neurons and glial cells. Treatment with H‐Exo markedly improved neurological function both in vivo and in vitro. Mechanistically, H‐Exo inhibits neuronal ferroptosis by preserving mitochondrial dynamics and alleviating oxidative stress. Transcriptomic analysis identified ARRDC3 as a previously unrecognized ferroptosis‐associated gene that was upregulated after ischemia but suppressed by H‐Exo treatment. ARRDC3 exacerbates neuronal ferroptosis by promoting Drp1‐dependent mitochondrial fragmentation. Proteomic profiling further identified CRYAB as an abundant exosomal cargo mediating the neuroprotective effects of H‐Exo. Pharmacological inhibition of CRYAB with NCI‐41356 partially reversed the anti‐ferroptotic effects of H‐Exo, confirming its essential role. Collectively, this study reveals the CRYAB–ARRDC3–Drp1 axis as a key regulator linking mitochondrial dynamics to ferroptosis and highlights H‐Exo as a promising non‐invasive therapeutic approach for ischemic stroke.
Ji et al. (Mon,) studied this question.
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