Insights Into the HIF-1α-Mediated NLRP3 Pyroptosis Pathway in the Regulation of Musculoskeletal Diseases in the High-Altitude Environment.

BACKGROUND: The high-altitude environment has features of hypobaric hypoxia, cold exposure, and strong ultraviolet radiation; all these factors lead to a high occurrence rate of musculoskeletal diseases, including osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP), and sarcopenia. Chronic inflammation and irreversible tissue damage are the core pathological characteristics shared by these disorders. MAIN BODY: Hypoxia-inducible factor-1α (HIF-1α), a core regulator of cellular oxygen homeostasis, is stabilized and overexpressed in high-altitude conditions. It organizes inflammatory reactions through cross-talk with NOD-like receptor protein 3 (NLRP3) inflammasome activation and the following pyroptosis. This review clarifies the molecular interaction between the HIF-1α-mediated inflammatory pathway and the NLRP3 inflammasome-driven pyroptosis in the pathogenesis of these four musculoskeletal diseases. We emphasize shared regulatory hubs: nuclear factor kappaB (NF-κB) activation, metabolic reprogramming, reactive oxygen species (ROS) accumulation, and the positive feedback loops they form-these loops strengthen inflammation in various tissues. We also discuss tissue-specific and population-level differences in HIF-1α responses, which explain different disease susceptibility between native high-altitude inhabitants and lowland migrants. CONCLUSION: Targeting the conserved HIF-1α/NLRP3 inflammatory axis through modulation of HIF-1α expression, NF-κB signaling, and oxidative stress may interrupt pathological pyroptosis and provide novel preventive and therapeutic strategies for musculoskeletal disorders in populations with long-term exposure to high-altitude stress.