Exploring New Horizons in Viral Myocarditis: The TRIM29-PERK Pathway

Xing and his team discovered that cardiotropic viruses highly induced TRIM29 and promoted PERK-mediated ER stress, apoptosis and reactive oxygen species responses that promote viral replication in cardiomyocytes in vitro. The researchers took a multifaceted approach, employing cardiomyocyte-specific TRIM29 knockout mice and pharmacological studies to dissect the complex relationship between TRIM29, PERK signaling and the immune response in myocarditis. This included gene editing, immunoprecipitation and various molecular biology assays. TRIM29 deletion or PERK inhibition with GSK2656157 protected mice from viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses and curbing inflammation and immunosuppressive monocytic myeloid-derived suppressor cells in vivo. Discovering the interaction between TRIM29 and PERK, and the role of PERK-mediated ER stress response in promoting viral replication and myocardial damage, provides valuable insights into the pathogenesis of viral myocarditis. These findings were published in Nature Communications. “We were pleased to learn that TRIM29 deficiency and pharmacological targeting of the TRIM29-PERK axis had a significant protective effect against viral myocarditis, reducing viral replication and symptoms,” Xing said. “Our findings make PERK inhibitor a promising drug to move forward to clinical trials for treating patients with viral myocarditis.”

The study's insights into the mechanisms underlying viral myocarditis, especially regarding PERK-mediated ER stress response and apoptosis, pave the way for further investigations. Researchers can now explore additional molecular pathways involved in the disease’s progression and better understand how viral infections interact with the body's immune responses. The research team’s next step is to prepare a PERK inhibitor for clinical trials and screen more effective drugs targeting the TRIM29-PERK axis for therapeutic treatment. Xing plans to collaborate with pharmaceutical companies to refine and optimize drugs targeting TRIM29, PERK, or related pathways identified in viral myocarditis. These collaborations are vital for translating promising preclinical findings into safe and effective treatments for patients.

By integrating various data sources, including genomic, proteomic and clinical data, Xing will identify distinct patient subgroups based on molecular signatures. “This personalized approach allows for tailored treatment strategies, ensuring that each patient receives the most effective therapy for their specific condition,” he emphasized. “By leveraging precision medicine, clinicians can optimize patient outcomes and minimize adverse effects, ushering in a new era of individualized care for viral myocarditis patients.”