The effect and mechanism of 6-hydroxygenistein in alleviating high-altitude cardiac injury via modulation of the PI3K/Akt signaling pathway

XIN Yu; SHI Zhi-qun; WANG Ge-ge; CHEN Ke-ming; JING Lin-lin

doi:10.20251/j.cnki.1003-3734.2026.04.008

Abstract：Objective:To elucidate the protective mechanism of 6-hydroxygenistein(6-OHG)against high-altitude induced heart injury(HAHI).Methods:6-OHG-related targets were predicted using SwissTargetPrediction,Similarity ensemble approach,SuperPred and PharmMapper databases.HAHI-related targets were obtained from GeneCards and OMIM databases.R package was used to draw Venn diagram.STRING 11.5 software was applied for constructing the protein-protein interaction network of the intersection targets.Cytoscape 3.8.0 software was used to screen core targets.GO and KEGG enrichment analysis were performed using DAVID database.AutoDock Vina software and PyMOL 3.0.0 software were used for molecular docking and visualization.The in vivo HAHI mouse model was established and for pharmacological intervention.Hematoxylin-eosin(HE)staining was used to observe the pathological changes of myocardial tissue.Oxidative stress indexes and inflammatory factors in myocardial tissues were detected using commercial assay kits.Expression of related proteins in myocardial tissue was detected by Western blot.Results:70 overlapping targets of 6-OHG and HAHI were screened,with AKT1,HSP90AA1,ACE and HMOX1 regarded as core targets.Molecular docking results showed strong binding affinities between 6-OHG and these core proteins.GO functional enrichment analysis and KEGG pathway enrichment analysis indicated that the regulation of oxidative stress and inflammatory response through the PI3K/Akt signaling pathway may play an important role in 6-OHG treatment of HAHI.In vivo animal experiments showed that high-altitude hypoxia exposure could induce pathological changes of myocardial tissue in mice,increase the levels of creatine kinase(CK),lactate dehydrogenase(LDH),lactic acid(LD),malondialdehyde(MDA),hydrogen peroxide(H2O2)and pro-inflammatory factors interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α),decrease the levels of glutathione(GSH),superoxide dismutase(SOD)and anti-inflammatory factor interleukin-10(IL-10),down-regulate the ratio of p-PI3K/PI3K and p-Akt/Akt in mouse myocardial tissue.6-OHG pretreatment could significantly reverse these changes.Conclusion:6-OHG alleviates oxidative stress and inflammatory response induced by high-altitude hypoxia exposure by activating PI3K/Akt signaling pathway,thereby alleviating HAHI.