Targeting GPER1 to suppress autophagy as a male-specific therapeutic strategy for iron-induced striatal injury

The functional outcome of intracerebral hemorrhage (ICH) in young male patients are poor than in premenopausal women. After ICH, ferrous iron accumulation causes a higher level of oxidative injury associated with autophagic cell death in striatum of male mice than in females. In rodent model of ferrous citrate (FC)-infusion that simulates iron accumulation after ICH, female endogenous estradiol (E(2)) suppresses autophagy via estrogen receptor α (ERα) and contributes to less injury severity. Moreover, E(2) implantation diminished the FC-induced autophagic cell death and injury in males, whose ERα in the striatum is less than females. Since, no sex difference of ERβ was observed in striatum, we delineated whether ERα and G-protein-coupled estrogen receptor 1 (GPER1) mediate the suppressions of FC-induced autophagy and oxidative injury by E(2) in a sex-dimorphic manner. The results showed that the ratio of constitutive GPER1 to ERα in striatum is higher in males than in females. The GPER1 and ERα predominantly mediated suppressive effects of E(2) on FC-induced autophagy in males and antioxidant effect of E(2) in females, respectively. This finding opens the prospect of a male-specific therapeutic strategy targeting GPER1 for autophagy suppression in patients suffering from iron overload after hemorrhage.