Stanniocalcin-1 confers neuroprotection against ischemic injury via calreticulin-dependent activation of the CAMKK2/AMPK/GSK-3β/Nrf2 pathway

This study explores the neuroprotective effects of Stanniocalcin-1 (STC1) in the context of ischemic stroke, a major cause of death and disability worldwide. Although STC1 is recognized for its cytoprotective properties, its role in cerebral ischemia/reperfusion (I/R) injury has not been fully characterized. Our objective was to clarify the effects and underlying mechanisms of STC1 using a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R). We administered recombinant human STC1 (rh-STC1) intranasally and assessed cerebral injury through various methods including neurological scoring, behavioral tests, and TUNEL/Nissl staining. Additionally, we evaluated markers of oxidative stress and ferroptosis. The results demonstrated that endogenous STC1 levels were decreased following ischemia. Treatment with rh-STC1 led to significant improvements in neurological function, reduction in infarct volume, and decreased permeability of the blood-brain barrier. Furthermore, rh-STC1 treatment mitigated neuronal apoptosis, oxidative stress, and ferroptosis. Mechanistically, rh-STC1 was found to interact with calreticulin (CRT), activating the CAMKK2/AMPK/GSK-3β/Nrf2 signaling pathway. Notably, the neuroprotective effects of rh-STC1 were abolished by an AMPK inhibitor. In conclusion, our findings indicate that rh-STC1 protects against cerebral I/R injury by inhibiting apoptosis and ferroptosis, primarily via the CRT/CAMKK2/AMPK/GSK-3β/Nrf2 pathway. This positions STC1 as a promising therapeutic target for ischemic stroke.