Background and PurposeIschaemic stroke is one of the most critical causes of death and disability worldwide, but its pharmacotherapies are currently lacking. This study aimed to investigate the effects of the sigma non-opioid intracellular receptor 1 agonist hypidone hydrochloride (YL-0919) on ischaemic stroke as well as the underlying mechanisms.Experimental ApproachMale mice were subjected to a middle cerebral artery occlusion (MCAO)/reperfusion (R) model to mimic ischaemic stroke injury. Neurological and cognitive functions were evaluated, and neuroinflammatory pathways in the medial prefrontal cortex and hippocampus were detected.Key ResultsMice subjected to MCAO exhibited obvious neurological and motor deficits, increased infarct volume and neuronal death in the acute phase, and severe cognitive impairment in the chronic phase. Administration of YL-0919 for seven consecutive days beginning within 7 h after MCAO significantly ameliorated the pathological changes described above. Further studies demonstrated that YL-0919 exerted its effect by suppressing absent in melanoma 2 (AIM2)-related inflammatory signals in MCAO mice and alleviated the neuronal deficits in the medial prefrontal cortex and hippocampus, thereby ameliorating chronic post-stroke cognitive impairment. This effect was eliminated by AIM2 overexpression in the medial prefrontal cortex and hippocampus.Conclusions and ImplicationsThis study highlights the extended therapeutic window for sigma non-opioid intracellular receptor 1 agonist administration during the acute phase of ischaemic stroke and further demonstrates that targeted inhibition of AIM2-mediated neuroinflammatory pathways may promote sustained cognitive rehabilitation in post-stroke survivors.