Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases

Wan-di Feng1, Yao Wang2,3, Tong Luo2, Xin Jia4, Cui-qin Cheng2, Hao-jia Wang2, Mei-qi Zhang4, Qi-qi Li4, Xue-jiao Wang2, Yi-ying Li2, Jin-yong Wang4, Guang-rui Huang2, Ting Wang1,3, An-long Xu1,2,3
1 Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
2 Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, China
3 National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for Metabolic Diseases, Beijing University of Chinese Medicine, Beijing 100029, China
4 Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
Correspondence to: An-long Xu:,
DOI: 10.1038/s41401-022-01028-9
Received: 18 July 2022
Accepted: 7 November 2022
Advance online: 15 December 2022


Recent evidence shows that targeting NLRP3 inflammasome activation is an important means to treat inflammasome-driven diseases. Scoparone, a natural compound isolated from the Chinese herb Artemisia capillaris Thunb, has anti-inflammatory activity. In this study we investigated the effect of scoparone on NLRP3 inflammasome activation in inflammatory diseases. In LPS-primed, ATP or nigericin-stimulated mouse macrophage J774A.1 cells and bone marrow-derived macrophages (BMDMs), pretreatment with scoparone (50 μM) markedly restrained canonical and noncanonical NLRP3 inflammasome activation, evidenced by suppressed caspase-1 cleavage, GSDMD-mediated pyroptosis, mature IL-1β secretion and the formation of ASC specks. We then conducted a transcriptome analysis in scoparone-pretreated BMDMs, and found that the differentially expressed genes were significantly enriched in mitochondrial reactive oxygen species (ROS) metabolic process, mitochondrial translation and assembly process, as well as in inflammatory response. We demonstrated in J774A.1 cells and BMDMs that scoparone promoted mitophagy, a well- characterized mechanism to control mitochondrial quality and reduce ROS production and subsequent NLRP3 inflammasome activation. Mitophagy blockade by 3-methyladenine (3-MA, 5 mM) reversed the protective effects of scoparone on mitochondrial damage and inflammation in the murine macrophages. Moreover, administration of scoparone (50 mg/kg) exerted significant preventive effects via inhibition of NLRP3 activation in mouse models of bacterial enteritis and septic shock. Collectively, scoparone displays potent anti-inflammatory effects via blocking NLRP3 inflammasome activation through enhancing mitophagy, highlighting a potential action mechanism in treating inflammasome-related diseases for further clinical investigation.
Keywords: scoparone; NLRP3 inflammasome; IL-1β; mitophagy; 3-methyladenine; inflammatory disease

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