Nicotinamide Mononucleotide Combined Glucose Counteracts Iron Overload–Induced Mitochondrial Dysfunction in Mice Under Hypobaric Hypoxia

Extreme high-altitude environment poses severe threats to human health, underscoring the urgent need for effective, safe metabolic interventions. Here, we demonstrate that combined regimen of nicotinamide mononucleotide (NMN) and glucose attenuates tissue injury and prevents body weight loss in mice under hypobaric hypoxia (HH). By leveraging a multi-tissue integrative atlas encompassing metabolome, lipidome, proteome, and phenotypic profiles, we identified HH-induced iron overload and oxidative stress as key pathological drivers. NMN plus glucose supplementation significantly counteracted metabolic disruptions across multiple tissues. Mechanistically, HH-induced, transferrin-inspired iron delivery, causing iron overload and oxidative stress, along with glutathione depletion and lipid peroxidation across multiple tissues. Notably, we observed no significant changes in the protein levels of ferroptotic markers including ACSL4, GPX4, and FSP1, although cannot rule out the possibility of activity alterations of these proteins. Nevertheless, NMN combined with glucose effectively reversed the ferroptosis-associated metabolic alterations and alleviated mitochondrial dysfunction. Collectively, our study provides a systems-level metabolic atlas and reveals that NMN combined glucose mitigates HH-induced multi-organ injury by suppressing ferroptosis through metabolic reprogramming, offering a therapeutic potential for high-altitude hypoxia.