From metabolic reprogramming to immune homeostasis: the bidirectional regulatory network of HIF-1α/HK2 and Th17/Treg in gout

Gout is a metabolic inflammatory disease whose pathogenesis involves the complex interaction between metabolic reprogramming and immune homeostasis imbalance. This review focuses on the bidirectional network through which the HIF-1 α /HK2 axis regulates the Th17/Treg balance via glycolytic reprogramming. Monosodium urate (MSU) crystals drive enhanced aerobic glycolysis in macrophages through the GLUT1-JNK-HIF-1 α signaling axis, where hexokinase 2 (HK2), as a metabolic checkpoint, connects glycolysis with NLRP3 inflammasome activation and neutrophil extracellular trap (NETosis)-induced M1 polarization. The glycolytic metabolic bias promotes the differentiation of T helper 17 (Th17) cells while inhibiting the generation of regulatory T (Treg) cells. In turn, cytokines derived from Th17/Treg cells reversely regulate the metabolic status of antigen-presenting cells, forming a feedback loop for inflammation amplification or resolution. Based on this network model, intervention strategies targeting the HIF-1 α /HK2/mTOR glycolytic axis and metabolic checkpoints (such as HK2, PKM2), including chaetocin, rapamycin, and various natural products, have shown therapeutic potential for restoring immune homeostasis. Current evidence mainly comes from animal models and in vitro experiments. In the future, it is necessary to use single-cell multi-omics technology to resolve the heterogeneity of the immunometabolic landscape, and to verify the dynamic regulatory mechanism of this network in the self-limiting resolution of gout inflammation.