2. Academic Validation
  3. Nepetin limits NLRP3 inflammasome activation and alleviates NLRP3-driven inflammatory diseases via PINK1-dependent mitophagy

Nepetin limits NLRP3 inflammasome activation and alleviates NLRP3-driven inflammatory diseases via PINK1-dependent mitophagy

  • Free Radic Biol Med. 2025 Feb 1:227:420-433. doi: 10.1016/j.freeradbiomed.2024.12.027.
Wen-Jie Bu 1,  Si-Si Li 1,  Chang Liu 1,  Yue-Hua Wang 1,  Jian-Rong Lu 1,  Chao-Run Dong 1,  Dong-Jie Zheng 1,  Zhe-Yu Fan 1,  Yi Yu 1,  Wei Zhang 2,  Yun-Long Bai 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, SKLFZCD, (State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China.
  • 2 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. Electronic address: zhangwei@gzucm.edu.cn.
  • 3 Department of Pharmacology, SKLFZCD, (State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Chinese Medicine Guangdong Laboratory, Guangdong, Hengqin, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China. Electronic address: ylbai@gzucm.edu.cn.
PMID: 39653129 DOI: 10.1016/j.freeradbiomed.2024.12.027
Abstract

The NLRP3 inflammasome plays a pivotal role in the progression of inflammatory diseases. Mitochondrial damage, oxidative stress and mitochondrial DNA (mtDNA) leak are the key upstream factors for NLRP3 inflammasome activation. Nepetin (Nep), a naturally occurring flavonoid found with anti-inflammatory properties; however, whether it can affect the NLRP3 inflammasome activation and its precise anti-inflammatory mechanism remains unclear. In this study, we demonstrated that Nep enhances PINK1-mediated ubiquitin phosphorylation, which promotes Mitophagy and subsequently inhibits NLRP3 inflammasome activation and Pyroptosis in macrophages. The administration of Nep to macrophages alleviated of mitochondrial damage, reduced mitochondrial superoxide production, restored mitochondrial membrane potential and prevented the mtDNA leakage. These findings provide compelling evidence for the antioxidant effect of Nep. Furthermore, the pivotal function of Mitophagy in the NLRP3 inflammasome inhibitory impact of Nep was substantiated through the utilisation of Mitophagy inhibitors and siRNA techniques. Notably, Nep increased survival and reduced organ damage in mice with systemic inflammation by inhibiting NLRP3 inflammasome activation. In addition, Nep suppressed NLRP3 inflammasome activation in obese mice, which led to reduced white adipose and liver inflammation, thereby ameliorating Insulin resistance. In conclusion, our findings suggest that Nep is a potent NLRP3 inflammasome inhibitor and a promising candidate for the development of anti-inflammatory therapies.

Keywords

IL-1β; Inflammatory disease; Mitophagy; NLRP3 inflammasome; Nepetin; PINK1.

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