{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:16:13Z","timestamp":1788441373690,"version":"build-2803163510"},"reference-count":42,"publisher":"IMR Press","issue":"8","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2024JJ5308"],"award-info":[{"award-number":["2024JJ5308"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Research Foundation of Education Bureau of Hunan Province, China","award":["23B0366"],"award-info":[{"award-number":["23B0366"]}]},{"name":"Central Guiding Local Science and Technology Development Fund Projects","award":["2025ZY01043"],"award-info":[{"award-number":["2025ZY01043"]}]},{"name":"Research Funds of Hangzhou Institute for Advanced Study, UCAS","award":["B05006C021007"],"award-info":[{"award-number":["B05006C021007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:Sustained activation of adipose tissue macrophages (ATMs) drives metabolic dysfunction in obesity, with the hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1)\/interleukin-1\u03b2 (IL-1\u03b2) 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-1\u03b2 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-1\u03b2. It dose-dependently suppressed IL-1\u03b2 in both LPS-induced and obese adipose tissue-conditioned medium-induced macrophage inflammation. Mechanistically, LJ-6 reduced HIF-1\u03b1 protein stability. Molecular docking and mutagenesis studies supported an interaction involving the Tyr92 and His197 residues of HIF-1\u03b1, and suggested that this interaction is critical for its inhibitory function on the HIF-1\u03b1\/IL-1\u03b2 axis.Conclusions:This study identifies the natural compound LJ-6 as a novel direct inhibitor of HIF-1\u03b1. By binding to HIF-1\u03b1, LJ-6 effectively suppresses the HIF-1\u03b1\/IL-1\u03b2 axis in macrophages, thereby reducing IL-1\u03b2-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.<\/jats:p>","DOI":"10.31083\/fbl53391","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:35:31Z","timestamp":1788438931000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting the HIF-1\u03b1\/IL-1\u03b2 Axis in Macrophages With the Novel Inhibitor LJ-6 Mitigates Adipose Tissue Inflammation in Cellular and Ex Vivo Models"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3154-5536","authenticated-orcid":true,"given":"Min","family":"Gao","sequence":"first","affiliation":[{"name":"Key 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"},{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China"},{"name":"University of Chinese Academy of Sciences, 100049 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, 226001 Nantong, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anran","family":"Chu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, 226001 Nantong, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisi","family":"Deng","sequence":"additional","affiliation":[{"name":"College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, 410128 Changsha, Hunan, China"},{"name":"Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, 410128 Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsong","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, 226001 Nantong, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, 226001 Nantong, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsheng","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, 226001 Nantong, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, 226001 Nantong, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, 226001 Nantong, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saifei","family":"Lei","sequence":"additional","affiliation":[{"name":"Key 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"},{"name":"University of Chinese Academy of Sciences, 100049 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wu","sequence":"additional","affiliation":[{"name":"Key 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"},{"name":"University of Chinese Academy of Sciences, 100049 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4419-7645","authenticated-orcid":true,"given":"Haowen","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China"},{"name":"University of Chinese Academy of Sciences, 100049 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"Key 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"},{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China"},{"name":"University of Chinese Academy of Sciences, 100049 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0915-4095","authenticated-orcid":true,"given":"Jinlong","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, 226001 Nantong, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China"},{"name":"University of Chinese Academy of Sciences, 100049 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8150-8134","authenticated-orcid":true,"given":"Chang","family":"Peng","sequence":"additional","affiliation":[{"name":"Key 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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Kong Y, Yang H, Nie R, Zhang X, Zuo F, Zhang H, et al. 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