SPP1 / OPN Alleviates Post‐Intracerebral Hemorrhage Depression and Cognitive Impairment via Nrf2 / BDNF Signaling Activation in Mice

Background Post‐stroke depression represents a prevalent neuropsychiatric complication following intracerebral hemorrhage (ICH), yet its underlying mechanisms remain less understood compared to ischemic stroke. Methods This translational investigation employed a multi‐omics approach, combining bioinformatics analysis of depression‐related (GSE214921) and ICH‐related (GSE18193) datasets from the GEO database with experimental validation. Using a collagenase‐induced striatal ICH murine model, we evaluated the effects of intranasal administration of osteopontin (OPN, encoded by SPP1) through neurobehavioral tests, histopathological evaluation, and molecular biology techniques. Results Integrated bioinformatics analysis identified the SPP1 signaling pathway as a potential key regulator in post‐ICH depression pathogenesis. In vivo, OPN treatment produced sustained neurobehavioral improvements at 28 days post‐ICH, significantly ameliorating neurological deficits, mitigating anxiety‐depressive behaviors, and enhancing spatial learning‐memory performance. Histopathological evaluation revealed OPN's multifaceted neuroprotective effects, including attenuated hippocampal neuroinflammation, preserved Nissl body integrity, and restored dendritic arborization complexity. Mechanistically, OPN exerted its therapeutic effects through activation of the Nrf2/BDNF signaling axis, as pharmacological inhibition of Nrf2 with ML385 completely abrogated both neuroprotection and BDNF upregulation. Conclusion Our study is the first to demonstrate the critical role of SPP1 signaling in post‐ICH depression through modulation of the Nrf2/BDNF pathway, providing novel therapeutic targets for clinical management of this debilitating neuropsychiatric sequela.