Xinhua He

Acute mountain sickness (AMS) arises from hypobaric hypoxia at high altitude and still lacks effective pharmacological treatments. Although hypoxic preconditioning via gradual ascent prevents AMS, the underlying molecular adaptations have not yielded therapeutics. Here, inspired by metabolic reprogramming during stepwise altitude adaptation, we screened for anti-hypoxia compounds and identified H0802 (N-(pyridin-2-yl) pyridine-2-carbothioamide) as the most promising candidate. H0802 markedly enhances hypoxic tolerance in mice, prolongs survival under acute hypoxia, improves survival during simulated high-altitude exposure, and attenuates hypoxia-induced lung injury, accompanied by combined anti-inflammatory and antioxidant effects. Transcriptomic profiling shows that H0802 elicits a gene expression signature resembling hypoxia, including key hypoxia-related genes (Edn1, Angptl4, Mt1, Gdf15, Slc7a5, and Hif-3α) involved in glucose and oxygen metabolism. Mechanistically, H0802 stabilizes endogenous hypoxia-inducible factor (HIF) proteins under normoxia by preventing ubiquitin-dependent degradation, thereby activating hypoxia-responsive genes. In vivo, H0802 pretreatment lowers circulating glucose and hepatic glycogen while increasing brain glucose uptake, suggesting a metabolic shift that preserves cerebral energy during acute hypoxic stress; it also modulates whole-body oxygen consumption. H0802 represents a candidate for anti-AMS therapy, and phenotypic optimization of H0802 provides a potential route for drug discovery.

Systemic lupus erythematosus (SLE) has a complex, multifactorial etiology, which contributes to a lack of definitive cure and limited treatment efficacy. Here, we report that cyclic GMP-AMP synthase (cGAS) is significantly activated in SLE patients. We further demonstrate that cGAS deletion protects mice from lupus-like symptoms induced by the TLR7 agonist imiquimod (IMQ). In a screen of 3,159 FDA-approved drugs, we identify the antiplatelet agent prasugrel as a potent cGAS inhibitor. Mechanistically, prasugrel disrupts the DNA-triggered liquid phase condensation and activation of cGAS via direct acetylation. Strikingly, we find that prasugrel exhibits remarkable efficacy in treating SLE in both mouse models and patient cells. Importantly, we report elevated plasma cyclic GMP-AMP (cGAMP) in SLE patients and identify it as a potential biomarker for predicting prasugrel response. Thus, our work elucidates the essential role of cGAS in SLE pathogenesis and presents prasugrel as a promising therapeutic option with immediate translational potential.

Human umbilical cord blood (HUCB) exhibits distinct characteristics compared to adult blood, offering significant potential for medical applications, particularly in antiaging therapies. However, the metabolic profile of HUCB relative to adult blood remains poorly understood. Moreover, the specific metabolites within HUCB that confer antiaging properties have yet to be identified. Here, we conducted an untargeted metabolomic analysis comparing cord plasma and adult plasma. Our results reveal a unique metabolic landscape in cord plasma, characterized by significant differences in 662 out of 1092 total compounds and 43 out of 59 total human metabolic pathways. Notably, 211 abundant cord metabolites decline with age, involving key aging‐related processes, including inflammation, oxidative stress, energy and nutrition metabolism, proteostasis and DNA damage responses, implicating their potential role in counteracting aging. Importantly, a proof‐of‐concept experiment demonstrates that a formula containing five of these metabolites (carnosine, taurocholic acid, inosine, L‐Histidine and N‐acetylneuraminic acid) significantly extends both lifespan and healthspan in C. elegans . Collectively, our findings provide novel insights into the distinctive characteristics of the human cord plasma metabolome and identify promising metabolites with therapeutic potential for antiaging and other cord blood‐based medical applications.