Protective effects of AKBA against hypoxia-induced cognitive dysfunction: potential involvement of SLC2A1, PTGS1, and BCL2L1

Introduction Hypoxia-induced cognitive impairment (HICI) is associated with neuroinflammation, oxidative stress, and gut microbiota dysbiosis, highlighting the need for effective neuroprotective interventions. Acetyl-11-keto-β-boswellic acid (AKBA), a bioactive triterpenoid derived from frankincense, possesses anti-inflammatory and antioxidant properties, but its protective effects against hypoxia-associated cognitive dysfunction remain insufficiently understood. Methods This study investigated the neuroprotective potential of AKBA administered concurrently with hypoxic exposure and explored its associated molecular alterations. Network pharmacology, transcriptomic analysis, molecular similarity assessment, molecular docking, and molecular dynamics simulations were integrated to identify and prioritize candidate proteins. The protective effects of AKBA were subsequently evaluated in mice exposed to normobaric hypoxia (12.7% O 2 ) for 10 days. Results AKBA administration attenuated hypoxia-associated cognitive deficits, accompanied by reduced inflammatory and oxidative stress markers, increased BDNF levels, decreased TUNEL-positive staining, and preservation of MBP immunoreactivity. These effects were associated with changes in cortical SLC2A1, PTGS1, and BCL2L1 expression, together with alterations in NF-κB- and Keap1/Nrf2-related protein levels. AKBA administration was also associated with changes in gut microbial composition, and exploratory correlation analyses suggested associations between selected bacterial taxa and cortical protein expression. Conclusion Collectively, these findings indicate that concurrent AKBA administration provides protection against hypoxia-associated cognitive dysfunction, potentially involving coordinated changes in inflammatory, antioxidant, and neurotrophic responses. However, the causal roles of the candidate proteins and gut microbiota alterations remain to be established through further functional investigations.