Abstract
Exertional heat stroke (EHS) poses a significant public health challenge because of its elevated rates of mortality and disability. Sex differences in incidence have been noted, and estrogen may be a contributing factor. The innovative G protein-coupled estrogen receptor (GPER) is recognized for its protective function in various diseases via the rapid non-genomic pathway associated with estrogen. The neuroprotective effects of the GPER agonist G1 are well known, but its potential to improve EHS-related brain injury has not been explored. We investigated whether G1 can improve EHS-related brain injury and clarified the mechanisms underlying its protective effects. Twenty-four hours after injury, transcriptome sequencing was conducted, disclosing varying gene expression patterns within the mouse hippocampus. Increased expression of stress-related genes within the endoplasmic reticulum (ER) of EHS mice was noted. The activation of GPER through G1 led to reduction in the levels of ER stress-related proteins, including CHOP, GRP78, and caspase-12. This, in turn, diminished neuronal apoptosis caused by ER stress and enhanced both the survival rate and cognitive abilities of EHS mice. Notably, the protective effects of G1 were diminished by the GPER blocker G15. GPER may represent a potential therapeutic target for brain injury associated with EHS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-44173-5.