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We previously reported the discovery of a novel, potent NLRP3 inhibitor, KBD3536, but its in vivo efficacy across different pathological conditions remains uncharacterized. Here, we systematically evaluated the in vivo efficacy of KBD3536 across diverse preclinical models of NLRP3-related pathologies. Methods: KBD3536 was evaluated in established rodent models of monosodium urate (MSU)-induced acute inflammation (mouse air pouch and rat gouty arthritis models), radiation-induced dermatitis (RID), and high-fat diet (HFD)-induced obesity. Results: In the MSU models, KBD3536 markedly suppressed local interleukin-1\u03b2 and interleukin-6 secretion in air pouch exudates and dose-dependently alleviated acute arthritis symptoms, including joint swelling and joint pain. In the RID model, KBD3536 significantly attenuated radiation-induced skin injury and ameliorated radiation-induced systemic weight loss. Under HFD challenge, early intervention with KBD3536 mitigated HFD-induced adiposity, early hepatic steatosis and its associated inflammatory responses, and preserved physical performance. Mechanistically, KBD3536 partially restored AMP-activated protein kinase \u03b11 (AMPK\u03b11) mRNA expression in adipose tissue and restored hepatic Cyp3a11 transcriptional activity. Conclusions: NLRP3 inhibitor KBD3536 exhibited broad-spectrum anti-inflammatory efficacy across multiple preclinical models, supporting its potential as a promising candidate for diverse NLRP3-related disorders.<\/jats:p>","DOI":"10.3390\/ph19071083","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:05:58Z","timestamp":1784077558000},"page":"1083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NLRP3 Inhibitor KBD3536 Attenuates Acute Inflammation, Radiation-Induced Skin Injury, and Early Metabolic Dysfunction in Preclinical Models"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0822-4167","authenticated-orcid":false,"given":"Xinying","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1777-6062","authenticated-orcid":false,"given":"Fei","family":"Ye","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Li","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1189-6433","authenticated-orcid":false,"given":"Hongzhu","family":"Chu","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyuan","family":"Peng","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueya","family":"Liang","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Zhong","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Wei","sequence":"additional","affiliation":[{"name":"Kangbaida (Sichuan) Biotechnology Co., Ltd., Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinglan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S1097-2765(02)00599-3","article-title":"The Inflammasome","volume":"10","author":"Martinon","year":"2002","journal-title":"Mol. 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