High‐Altitude Hypoxia Activates JNK ‐p53 Signaling: Linking Hippocampal Energy Crisis to Cognitive Impairment

BACKGROUND: Chronic high-altitude hypoxia impairs hippocampal memory, yet population-level dose-response relationships and the molecular mechanisms linking hypoxic stress to energy metabolic collapse remain poorly defined. METHODS: We conducted a cross-sectional study of 2819 residents (living at altitudes between 3000 and 5000 m). In parallel, we established a rat model of sustained hypobaric hypoxia (6000 m, 1-28 days) and applied pharmacological intervention using the JNK inhibitor JNK-IN-8. Metabolomic profiling, transmission electron microscopy, and molecular analyses were performed to assess metabolic reprogramming, mitochondrial ultrastructure, and signaling pathways. RESULTS: Residents at > 4000 m exhibited 91% higher memory impairment risk. Chronic hypoxia activated JNK-p53-Bim signaling, driving mitophagy-to-apoptosis transition, mitochondrial cristae disruption, and 73% ATP depletion by Day 28. JNK-IN-8 partially restored ATP and suppressed p53. HIF-2α/PHD2 colocalization indicated parallel adaptive signaling. CONCLUSIONS: Chronic hypoxia induces memory impairment via JNK-mediated mitochondrial dysfunction. JNK inhibition offers therapeutic potential, while concurrent HIF-2α/PHD2 activation suggests a complex balance between hypoxic injury and adaptation.