# ROS-Mediated Necroptosis Promotes Coxsackievirus B3 Replication and Myocardial Injury

## TL;DR

This study shows that Coxsackievirus B3 causes heart damage by triggering a type of cell death called necroptosis, which is linked to increased reactive oxygen species and reduced antioxidant defenses.

## Contribution

The study identifies a novel mechanism by which Coxsackievirus B3 induces necroptosis through ROS accumulation and Nrf2/HO-1 pathway suppression.

## Key findings

- CVB3 infection increases RIP1 and RIP3 expression, markers of necroptosis, in cells and mouse heart tissue.
- ROS levels rise and the Nrf2/HO-1 antioxidant pathway is suppressed during CVB3 infection.
- Inhibiting necroptosis or ROS reduces cell death, viral replication, and heart injury in infected mice.

## Abstract

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.