Yuzi Jin,1,* Joshua S Fleishman,2,* Yudong Ma,3 Xiaoqing Jing,4 Qin Guo,1 Weiguang Shang,1 Hongquan Wang5 

1Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110020, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, 11439, USA; 3Department of Critical Care Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110020, People’s Republic of China; 4Department of Pediatrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China; 5Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yuzi Jin, Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110020, People’s Republic of China, Email Jinyz@cdmc.edu.cn

Abstract: Cardiac or myocardial dysfunction induced by sepsis, known as sepsis-induced cardiomyopathy or sepsis-induced myocardial injury (SIMI), is a common complication of sepsis and is associated with poor outcomes. However, the pathogenesis and molecular mechanisms underlying SIMI remain poorly understood, requiring further investigations. Emerging evidence has shown that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to SIMI. Compounds that inhibit NLRP3-associated pyroptosis may exert therapeutic effects against SIMI. In this review, we first outlined the principal elements of the NLRP3 signaling cascade and summarized the recent studies highlighting how NLRP3 activation contributes to the pathogenesis of SIMI. We outlined selective small-molecule modulators that function as NLRP3 inhibitors and delineated their mechanisms of action to attenuate SIMI. Finally, we discuss the major limitations of the current therapeutic paradigm and propose possible strategies to overcome them. This review highlights the pharmacological inhibition of SIMI as a promising therapeutic strategy.

Keywords: sepsis, sepsis-induced myocardial injury, NLRP3, pyroptosis, bioactive compounds