Integrated UPLC-QE/MS, Network Pharmacology, and Transcriptomics Reveal the Protective Effects and Mechanisms of Ganoderma leucocontextum ethanol Extract on Acute altitude-related kidney injury

Background: This study aims to investigate the protective effects and mechanisms of Ganoderma leucocontextum ethanol extract (GLE) against acute altitude-induced kidney injury (AAKI) using an integrated strategy.Methods: A mouse AAKI model was established by simulating 5500 m altitude exposure. Renal function, histopathology, and apoptosis were assessed. The bioactive components of GLE were identified by UPLC-QE-MS. Network pharmacology and renal transcriptomics were integrated to pinpoint core pathways, with key findings validated by molecular docking and Western blot.Results: GLE significantly improved renal function, oxidative stress, and pathological damage in AAKI mice. It also remarkably attenuated renal apoptosis. Twenty-five bioavailable components were identified in GLE. Integrated analysis revealed that GLE modulated 72 differentially expressed genes and the MAPK signaling pathway was highlighted as central. Molecular docking confirmed stable binding between GLE components and the key target DDIT3. Western blot validated that GLE inhibits the MAPK/DDIT3-mediated apoptotic pathway.Conclusion: GLE alleviates high-altitude induced kidney injury likely through the multi-component synergistic inhibition of the MAPK/DDIT3 pathway, reducing apoptosis and oxidative stress.