OBJECTIVE: To investigate the pathogenesis of high-altitude cerebral edema (HACE) and develop new therapeutic strategies. METHODS: Male Sprague-Dawley (SD) rats of 6 weeks old were selected and placed in a hypobaric chamber. The rats were exposed to the high-altitude environment of 7000 m above sea level for 3 days for HACE modeling. Whether the HACE model was successfully established in the rats was evaluated by measuring brain water content, the degree of disruption to the blood-brain barrier (BBB), and brain tissue Nissl staining. The experimental animals were divided into four groups, with 28 rats in each group. The blank control group was exposed to a normobaric and normoxic environment simulating the conditions at 500 m above sea level for 3 d. The other groups, including a model group (the HACE group), a bumetanide group (the positive control group), and a XH-6003 treatment group, were placed at an altitude of 7000 m above sea level and were injected with normal saline, bumetanide, and XH-6003, a new type of Na-K-2Cl cotransporter 1 (NKCC1) inhibitor, via the tail vein, respectively, twice daily for 3 d. The experimental animals were taken out of the hypobaric chamber for testing after 3 d. The primary outcome measures included brain water content, BBB permeability, changes in brain tissue morphology, and the expression levels of aquaporin-4 (AQP4) and NKCC1. The secondary outcome measures included behavioral changes, apoptosis, and oxidative stress markers. RESULTS: The HACE rat model was successfully established. The model group exhibited increased brain water content ( CONCLUSION: HACE is associated with the activation of the NKCC1/AQP4 pathway. Inhibition of this pathway alleviates brain edema, BBB disruption, and neuronal and glial cell damage. These findings suggest that XH-6003 holds potential as a therapeutic strategy for HACE at the cellular and molecular levels, but its effects in improving HACE-related behavioral disorders warrant further investigation.