biostudies-literatureLiu CNational Natural Science Foundation of China8782https://www.ebi.ac.uk/biostudies/studies/S-EPMC12469424biostudies-literatureUnknown26(18)The mechanisms underlying the abnormal activation of microglia affecting cognitive function under high-altitude hypobaric hypoxia (HAHH) have not been fully elucidated. This study aims to investigate the effects of HAHH on the expression of the receptor for advanced glycation end-products (RAGE) in hippocampal microglia of mice and to explore the role of RAGE inhibitors in alleviating HAHH-induced microglial inflammation and cognitive impairment. Mice were exposed to HAHH via a multi-environment simulation chamber, and RNA sequencing, qPCR, WB, flow cytometry and immunohistochemistry showed that HAHH exposome significantly increased RAGE expression in hippocampal microglia of mice (<i>p</i> < 0.001 vs. normoxia), which was closely related to microglial neuroinflammatory responses. RAGE inhibitor (FPS-ZM1) alleviated HAHH-induced microglial inflammation (TNF-α decreased by 64%, <i>p</i> < 0.001; CD86⁺ cells decreased by 42%, <i>p</i> < 0.001) and improved cognitive function in mice (Y-maze novel arm time: 28.08 ± 5.14 s vs. hypoxia 19.67 ± 4.68 s, <i>p</i> = 0.016; NORT recognition index: 0.52 ± 0.05 vs. hypoxia 0.33 ± 0.07, <i>p</i> < 0.001). Mechanistic studies revealed that RAGE inhibitors reduced microglial inflammation by inhibiting the MAPK pathway and decreasing nuclear translocation of NF-κB p65. Furthermore, high-mobility group box 1 (HMGB1) expression increased under hypoxic conditions (<i>p</i> < 0.001 vs. normoxia) and positively regulated RAGE expression. HMGB1 inhibitors reduced RAGE expression and attenuated HAHH-induced microglial inflammation. Overall, the HAHH exposome induces microglial inflammation via the HMGB1-RAGE-NF-κB pathway. RAGE and HMGB1 inhibitors may serve as novel therapeutic strategies to mitigate HAHH-induced cognitive impairment, providing a theoretical basis for the treatment of cognitive impairment.International journal of molecular sciencesInhibition of the HMGB1-RAGE Axis Attenuates Microglial Inflammation and Ameliorates Hypoxia-Induced Cognitive Impairment.PMC1246942482230063 and 82303493Zou YZhang JChen MZhang HLuo WLiu CGuan RDu MfalseInhibition of the HMGB1-RAGE Axis Attenuates Microglial Inflammation and Ameliorates Hypoxia-Induced Cognitive Impairment.The mechanisms underlying the abnormal activation of microglia affecting cognitive function under high-altitude hypobaric hypoxia (HAHH) have not been fully elucidated. This study aims to investigate the effects of HAHH on the expression of the receptor for advanced glycation end-products (RAGE) in hippocampal microglia of mice and to explore the role of RAGE inhibitors in alleviating HAHH-induced microglial inflammation and cognitive impairment. Mice were exposed to HAHH via a multi-environment simulation chamber, and RNA sequencing, qPCR, WB, flow cytometry and immunohistochemistry showed that HAHH exposome significantly increased RAGE expression in hippocampal microglia of mice (<i>p</i> < 0.001 vs. normoxia), which was closely related to microglial neuroinflammatory responses. RAGE inhibitor (FPS-ZM1) alleviated HAHH-induced microglial inflammation (TNF-α decreased by 64%, <i>p</i> < 0.001; CD86⁺ cells decreased by 42%, <i>p</i> < 0.001) and improved cognitive function in mice (Y-maze novel arm time: 28.08 ± 5.14 s vs. hypoxia 19.67 ± 4.68 s, <i>p</i> = 0.016; NORT recognition index: 0.52 ± 0.05 vs. hypoxia 0.33 ± 0.07, <i>p</i> < 0.001). Mechanistic studies revealed that RAGE inhibitors reduced microglial inflammation by inhibiting the MAPK pathway and decreasing nuclear translocation of NF-κB p65. Furthermore, high-mobility group box 1 (HMGB1) expression increased under hypoxic conditions (<i>p</i> < 0.001 vs. normoxia) and positively regulated RAGE expression. HMGB1 inhibitors reduced RAGE expression and attenuated HAHH-induced microglial inflammation. Overall, the HAHH exposome induces microglial inflammation via the HMGB1-RAGE-NF-κB pathway. RAGE and HMGB1 inhibitors may serve as novel therapeutic strategies to mitigate HAHH-induced cognitive impairment, providing a theoretical basis for the treatment of cognitive impairment.2025-01-01T00:00:00Z2025 Sep2026-05-01T03:21:29.484Z2026-05-01T03:11:14.675ZS-EPMC124694244100935110.3390/ijms26188782