Neuroprotective mechanism of salidroside derivative SHPL-49 involves amelioration of brain lipid metabolism disorder to mitigate ferroptosis in a rat model of pMCAO

• Oral administration of SHPL-49 confers neuroprotection in ischemic stroke rats. • SHPL-49 mitigates brain lipid metabolism disorders. • Iron-dependent ferroptosis is a central target of SHPL-49. • Preclinical evidence for oral efficacy and multi-mechanistic action. Ischemic stroke, characterized by high incidence and mortality, severely endangers human health. This study investigated the neuroprotective potential of salidroside derivative SHPL-49 (NB-SHPL-49-A-3, Supplementary Material 1). Male Sprague-Dawley rats with permanent middle cerebral artery occlusion (pMCAO) received oral SHPL-49 at 60 mg/kg and 90 mg/kg for 14 days, with Butylphthalide (NBP) as a positive control. In vivo, neurological function, infarct volume, cognitive ability, and grip strength were evaluated, and lipid metabolism and the ferroptosis-related ACSL4-GPX4 pathway were analyzed. In vitro PC12 cell oxygen-glucose deprivation (OGD) models were established. Results showed that 90 mg/kg SHPL-49 significantly improved neurological and cognitive functions, reduced infarct volume, regulated lipid metabolism, and inhibited ferroptosis via the ACSL4-GPX4 pathway. In conclusion, 90 mg/kg oral SHPL-49 protected against neurodegeneration and reversed lipid metabolism disorder in ischemic stroke rats.