This report covers all experiments in 2016-2018, to date. The project is currently in 1 yr, no-cost extension. Over 128 male and female mice were used to evaluate the physiological responses to exertional heat stroke (EHS) and recovery (14 days). Females outperformed the males in distance run, mechanical work and time in the heat by 50-100%. Metabolomics measurements revealed striking differences between male and female mice with regard to myocardial lipid metabolism and hormonal responses. Males underwent a metabolic switch to beta-oxidation that was sustained for 14 days. We have recently studied 32 additional female mice to more closely compare these metabolomic responses in males. The results suggest that the performance advantage of females may relate to their alternative metabolic pathways. It is possible that this could translate to Warfighters ability to perform in the heat if they converted to a more lipid-metabolic state. We also studied the influence of 48 hours of ibuprofen (IBU) ingestion on performance and intestinal injury in male and female mice. IBU increased the max core temperature prior to collapse in EHS. This was associated with increases in the exercise time (tolerance) during the last phases of the EHS protocol. We saw modest effects of IBU on intestinal injury, both histologically and through biomarkers. The primary source of injury was from EHS alone. Recent experiments involved the study of diclofenac, an alternative NSAID a diclofenac-H2S donor (ATB-337). Neither diclofenac nor ATB-337 had any impact on EHS performance. However, ATB337 significantly elevated biomarkers of intestinal injury (FABP2) compared to diclofenac alone. Interestingly, diclofenac reduced circulating white blood cells during EHS but this effect was attenuated by ATB337. Overall, the results suggest that the H2ScontainingNSAIDs may not provide a protective role in EHS.