Metformin Inhibits Inflammation by Targeting the NLRP3 Inflammasome: Linking NF-κB/NEK7/AMPK Signaling to Mitochondrial Function

Dingyi Ning,1,2 Chenxin Jiang,1 Jiangyan Zeng,3 Fanyun Zeng,3 Xuehong Zheng,4 Panpan Xia,5 Yunkun Liu,4 Xin Huang,4 Deju Zhang,6 Xiao Liu,7 Jing Zhang,8 Peng Yu4 1Queen Mary School, Nanchang University, Nanchang, 330006, People’s Republic of China; 2The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang, 330006, People’s Republic of China; 3The First Clinical Medical College of Gannan Medical University, Ganzhou, 341000, People’s Republic of China; 4Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang, 330006, People’s Republic of China; 5Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang, China; Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, People’s Republic of China; 6Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Hong Kong, People’s Republic of China; 7Department of Cardiovascular Medicine, The Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 8Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of ChinaCorrespondence: Peng Yu, Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi province, People’s Republic of China, Tel +011 86 18162106127, Fax +011 86 791 86120120, Email [email protected]: Metformin, the first-line treatment for type 2 diabetes, has significant anti-inflammatory functions in addition to controlling blood glucose levels. Although metformin has been proven to inhibit NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, the function of mitochondria in this effect has not been fully studied. This review summarizes studies on metformin that could regulate inflammation progression through the Toll-like Receptor 4/Nuclear Factor Kappa B (TLR4/NF-κB) pathway, NIMA-related kinase 7 (NEK7) pathway, AMPK pathway, and Janus kinase 2-Signal Transducer and Activator of Transcription (JAK2-STAT) pathway, with the involvement of mitochondria. The effects of metformin on the mitochondria block the key steps of NLRP3 inflammation activation, including NEK7 assembly, reactive oxygen species (ROS) activation, reduced thioredoxin-interacting protein (TXNIP) expression, and caspase 1-mediated IL-1β/IL-18 maturation. Importantly, we propose that metformin improves the pathological development of common multi-organ diseases by regulating NLRP3-inflammation pathways. These findings highlight the promising treatment potential of metformin in diseases driven by inflammasomes and make it meaningful to implement clinical trials to evaluate its efficacy in NLRP3 inflammasome-driven pathologies beyond diabetes. Keywords: metformin, inflammasome, signaling pathways, elucidation of mechanism, multi-organ diseases