{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:58:14Z","timestamp":1785437894864,"version":"3.56.0"},"reference-count":33,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Zhejiang Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["LDT23H19012H19"],"award-info":[{"award-number":["LDT23H19012H19"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"award":["LDT23H19012H19"],"award-info":[{"award-number":["LDT23H19012H19"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong","doi-asserted-by":"publisher","award":["ZR2023LZY003"],"award-info":[{"award-number":["ZR2023LZY003"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China","award":["JYB2025XDXM609"],"award-info":[{"award-number":["JYB2025XDXM609"]}]},{"name":"Fundamental Research Funds for Central Universities","award":["226-2025-00009"],"award-info":[{"award-number":["226-2025-00009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: The NLRP3 inflammasome drives pathological inflammation in various diseases. PINK1\/Parkin-associated mitophagy serves as a critical negative regulator of NLRP3 activation, yet pharmacological enhancers remain scarce. Muscone, a natural macrocyclic ketone with blood\u2013brain barrier permeability, exhibits potent anti-inflammatory properties; however, its mechanistic role within the NLRP3-mitophagy axis remains undefined. Methods: LPS\/ATP-stimulated macrophages were employed to assess stage-specific effects of muscone on NLRP3 priming (NF-\u03baB signaling, NLRP3, and pro-IL-1\u03b2 expression) and activation (ASC oligomerization, ASC\u2013pro-caspase 1 complex formation, and IL-1\u03b2 secretion). RNA sequencing and bioinformatic analysis were performed for pathway enrichment. Mitophagy was characterized by MitoSOX Red staining for mt-ROS detection, electron microscopy, Western blotting of LC3B-II in isolated mitochondria and PINK1 and Parkin in whole-cell lysates, and live-cell mitochondria\u2013lysosome tracking. In vivo protective efficacy was assessed in an LPS-induced endotoxemia mouse model. Results: Muscone dose-dependently suppressed both the priming and activation stages of the NLRP3 inflammasome, maximally reducing IL-1\u03b2 secretion by ~60% at 50 \u03bcM. Mechanistically, muscone amplified PINK1\/Parkin-associated mitophagy, scavenging excessive mt-ROS and attenuating NLRP3 activation. These effects were corroborated by RNA-seq and comprehensive functional assays. In vivo, muscone (30 mg\/kg) significantly improved survival (3\/8 mice alive at 98 h when all LPS controls had died; 2\/8 survived to the 132-h endpoint), with concomitant enhancement of mitophagy markers in peritoneal macrophages. Conclusions: Muscone functions as a PINK1\/Parkin-associated mitophagy enhancer that maintains mitochondrial quality control during NLRP3-driven inflammatory responses. Its unique macrocyclic structure and blood\u2013brain barrier permeability provide a promising scaffold for developing therapeutics against inflammatory disorders associated with NLRP3 inflammasome activation.<\/jats:p>","DOI":"10.3390\/ph19060816","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T05:33:54Z","timestamp":1779687234000},"page":"816","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Muscone Promotes PINK1\/Parkin-Associated Mitophagy to Suppress NLRP3 Inflammasome Activation: Implications for Endotoxemia Therapy"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6435-7274","authenticated-orcid":false,"given":"Ziwei","family":"Yan","sequence":"first","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minrui","family":"Li","sequence":"additional","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentian","family":"Hua","sequence":"additional","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxue","family":"Cao","sequence":"additional","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Li","sequence":"additional","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Che","sequence":"additional","affiliation":[{"name":"Xiamen Traditional Chinese Medicine Co., Ltd., Xiamen 361100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1743-8983","authenticated-orcid":false,"given":"Xiyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Xiamen Traditional Chinese Medicine Co., Ltd., Xiamen 361100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Lai","sequence":"additional","affiliation":[{"name":"Xiamen Traditional Chinese Medicine Co., Ltd., Xiamen 361100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3676-9183","authenticated-orcid":false,"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"},{"name":"Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China"},{"name":"Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9428-6390","authenticated-orcid":false,"given":"Guofang","family":"Shen","sequence":"additional","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"},{"name":"Hangzhou Institute for Food and Drug Control, Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1642-9202","authenticated-orcid":false,"given":"Jing","family":"Qian","sequence":"additional","affiliation":[{"name":"Pharmaceutical Informatics Institute, School of Pharmacy, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome: Molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat. 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