Intervention with Necrostatin-1 or N-acetylcysteine attenuated cell death, suppressed viral replication, and ameliorated myocardial injury in CVB3-infected mice.
Does Necrostatin-1 or N-acetylcysteine reduce cell death, viral replication, and myocardial injury in HeLa cells and mouse models of Coxsackievirus B3 infection?
Inhibition of necroptosis or ROS scavenging attenuates CVB3-induced myocardial injury and viral replication, suggesting a potential therapeutic strategy for viral myocarditis.
Coxsackievirus B3 (CVB3) is a primary causative agent of viral myocarditis (VMC), which can lead to both acute and chronic cardiac inflammation accompanied by progressive heart failure and arrhythmias. Although CVB3 has been implicated in various forms of programmed cell death, whether it triggers necroptosis and the underlying mechanisms remains unclear. This study aimed to investigate the role and mechanism of CVB3-induced necroptosis and its effect on viral replication. Using both in vitro and in vivo models, we demonstrated that CVB3 infection significantly upregulates the expression of key necroptotic markers RIP1 and RIP3 in HeLa cells and mouse myocardial tissues. This upregulation was accompanied by elevated intracellular reactive oxygen species (ROS) levels and suppression of the Nrf2/HO-1 antioxidant pathway. Intervention with the necroptosis inhibitor Necrostatin-1 (Nec-1) or the ROS scavenger N-acetylcysteine (NAC) markedly attenuated cell death, suppressed viral replication, and ameliorated myocardial injury and inflammatory responses in infected mice. Mechanistically, CVB3 inhibits the Nrf2/HO-1 pathway, thereby inducing substantial ROS accumulation that promotes necroptosis. This effect can be reversed by NAC treatment. Our study reveals a novel mechanism through which CVB3 induces ROS-dependent necroptosis via the suppression of the Nrf2/HO-1 pathway, providing new insights into the pathogenesis of viral myocarditis and suggesting potential therapeutic strategies.
Huang et al. (2025) studied Viral myocarditis (Coxsackievirus B3 infection). Necrostatin-1 (Nec-1) or N-acetylcysteine (NAC) was evaluated on Cell death, viral replication, myocardial injury, and inflammatory responses. Intervention with Necrostatin-1 or N-acetylcysteine attenuated cell death, suppressed viral replication, and ameliorated myocardial injury in CVB3-infected mice.