This study aimed to evaluate the pharmacokinetics of acipimox in rats under simulated high altitude hypoxia conditions. A sensitive and reliable LC–MS/MS method has been established for the quantitation of acipimox in rat plasma and tissue homogenate and validated according to the guidelines of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Western blotting and enzyme linked immunosorbent assay (ELISA) were used to investigate the expression of lipid metabolism-related proteins and free fatty acid (FFA) levels, respectively. Cell viability was detected using a Cell Counting kit-8 assay (CCK-8). The method was then successfully applied in a pharmacokinetic comparison between normoxic and hypoxic rats. The results indicated that there were significant differences in the main pharmacokinetics parameters of acipimox between normoxic and hypoxic rats. HCAR2 expression in the hypoxia group was upregulated compared to that in the normoxia group and the levels of FFA decreased more in the hypoxia group. Under the hypoxia condition, the proliferation of HK2 cells was inhibited with increasing concentrations of acipimox. The results provide important and valuable information for the safety and efficacy of acipimox, which indicated that the dosage of acipimox might be adjusted appropriately during clinical medication in hypoxia.

Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), Tripterygium wilfordii Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor angiogenesis effect remain unclear. The process of angiogenesis needs lots of energy supply, which mostly derives from mitochondria, the “energy factory” in our body. This study shows that celastrol exerts visible suppression on tumor growth and angiogenesis in a cell-derived xenograft (CDX). Likewise, it reduced the tube formation and migration of human umbilical vein endothelial cells (HUVECs), suppressed the energy metabolism of mitochondria in the Seahorse XF Mito Stress Test, and triggered mitochondrial fragmentation and NF-κB activation. Mechanically, celastrol downregulated the expression of mitochondrial-sharping protein optic atrophy protein 1 (OPA1), which was further estimated by the OPA1 knockdown model of HUVECs. Specifically, celastrol directly suppressed OPA1 at the mRNA level by inhibiting the phosphorylation of STAT3, and stattic (STAT3 inhibitor) showed the same effects on OPA1 suppression and anti-angiogenesis activity. Overall, this study indicates that celastrol inhibits tumor angiogenesis by suppressing mitochondrial function and morphology via the STAT3/OPA1/P65 pathway and provides new insight for mitochondrion-targeted cancer therapy.

Chronic exposure to high altitudes causes pathophysiological cardiac changes that are characterized by cardiac dysfunction, cardiac hypertrophy, and decreased energy reserves. However, finding specific pharmacological interventions for these pathophysiological changes is challenging. In this study, we identified tetramethylpyrazine (TMP) as a promising drug candidate for cardiac dysfunction caused by simulated high-altitude exposure. By utilizing hypobaric chambers to simulate high-altitude environments, we found that TMP improved cardiac function, alleviated cardiac hypertrophy, and reduced myocardial injury in hypobaric hypoxic mice. RNA sequencing showed that TMP also upregulated heart-contraction-related genes that were suppressed by hypobaric hypoxia exposure. Mechanistically, TMP inhibited hypobaric hypoxia-induced cardiac Ca²⁺/calmodulin-dependent kinase II (CaMKII) activation and exerted cardioprotective effects by inhibiting CaMKII. Our data suggest that TMP application may be a promising approach for treating high-altitude-induced cardiac dysfunction, and they highlight the crucial role of CaMKII in hypobaric hypoxia-induced cardiac pathophysiology.

High-altitude environments, characterized by hypoxia, low temperature, and intense ultraviolet radiation, profoundly disrupt host intestinal homeostasis and reshape the gut microbiota, thereby influencing immune regulation and acclimatization. This review systematically summarizes the dynamic compositional and functional changes in the gut microbiota in high-altitude natives, immigrant populations, short-term visitors, and relevant animal models. Current evidence indicates that long-term high-altitude adaptation is associated with directional microbial remodeling, including the enrichment of anaerobic and short-chain fatty acid (SCFA)-associated taxa, which may support energy metabolism and immune homeostasis. In contrast, acute high-altitude exposure more readily induces dysbiosis, impairs intestinal barrier integrity, and promotes the translocation of endotoxins and bioactive metabolites. Mechanistically, the gut microbiota and its metabolites participate in high-altitude adaptation and high-altitude-related disease pathogenesis by modulating barrier function, inflammatory responses, oxidative stress, and immune signaling, and by mediating interorgan communication—characterized by metabolite-driven systemic inflammation or tolerance—through the gut–lung, gut–heart, gut–brain, gut–kidney, and gut–testis axes. SCFAs, bile acids, amino acid-derived metabolites, and succinic acid may control immune homeostasis and inflammatory responses through pathways including TLR4/NF-κB and NLRP3. Although the causal relationships, core microbial effectors, and population-specific heterogeneity remain incompletely defined, microbiota-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, have shown promise for promoting acclimatization and preventing high-altitude-related disorders. Overall, this review provides an integrated framework linking environmental stress, gut microbial ecology, and host immune–metabolic adaptation at high altitude, and highlights future directions for mechanistic and translational research in high-altitude medicine.