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Targeting the HIF-1α/IL-1β Axis in Macrophages With the Novel Inhibitor LJ-6 Mitigates Adipose Tissue Inflammation in
Min Gao1,2,3, Mengyuan Liu4, Anran Chu4
1Key Laboratory of Glyco-drug Research of Zhejiang Province, School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 310024 Hangzhou, Zhejiang, China.
Background:
Sustained activation of adipose tissue macrophages (ATMs) drives metabolic dysfunction in obesity, with the hypoxia-inducible factor-1α (HIF-1α)/interleukin-1β (IL-1β) axis being a core signaling pathway. However, specific strategies targeting this axis are still lacking. Here, we aimed to identify novel compounds capable of disrupting this pathway.
Methods:
We screened a natural product library for inhibitors of IL-1β expression in macrophages. The hit compound LJ-6 was then evaluated in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) and in a physiologically relevant model using conditioned medium from obese adipose tissue. Mechanism of action was investigated via Western blotting, molecular docking, dynamics simulations, and hypoxia-response element (HRE)-luciferase reporter assays with site-directed mutagenesis.
Results:
LJ-6 was identified as a potent inhibitor of IL-1β. It dose-dependently suppressed IL-1β in both LPS-induced and obese adipose tissue-conditioned medium-induced macrophage inflammation. Mechanistically, LJ-6 reduced HIF-1α protein stability. Molecular docking and mutagenesis studies supported an interaction involving the Tyr92 and His197 residues of HIF-1α, and suggested that this interaction is critical for its inhibitory function on the HIF-1α/IL-1β axis.
Conclusions:
This study identifies the natural compound LJ-6 as a novel direct inhibitor of HIF-1α. By binding to HIF-1α, LJ-6 effectively suppresses the HIF-1α/IL-1β axis in macrophages, thereby reducing IL-1β-driven inflammatory responses in cellular and ex vivo models of obesity-associated adipose tissue inflammation, and thus represents a promising lead compound for therapeutic development.
