ORIGINAL RESEARCH article
Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1674049
Exploring ceRNA Mechanisms in COVID-19 mRNA Vaccine-Induced Myocarditis: Implications for Future Vaccine Design
Provisionally accepted
- Peking University Hospital of Stomatology, Beijing, China
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The emergence of Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitated the rapid development of effective vaccines, with mRNA vaccines demonstrating high efficacy and accelerated production timelines. However, reports of myocarditis following mRNA vaccination have raised safety concerns, and the underlying molecular mechanisms remain poorly understood. Here, we transfected human AC16 cardiomyocytes with in vitro transcribed (IVT) COVID-19 mRNA modified with N1-methylpseudouridine (m1Ψ) to assess its inflammatory potential. The results demonstrated that IVT mRNA elicited a robust inflammatory response in cardiomyocytes, markedly upregulating the proinflammatory cytokine IL-6 (~2-fold). Under inflammatory conditions, IVT mRNA further exacerbated IL-6 secretion (~2-fold) and increased cardiomyocyte apoptosis (~1.3-fold). Additionally, IVT mRNA significantly elevated the levels of myocardial injury biomarkers, specifically Creatine Kinase-MB (CK-MB, ~1.5-fold) and cardiac troponin I (c-TnI, ~2-fold). Mechanistically, IVT mRNA functions as a competing endogenous RNA (ceRNA) for hsa-let-7f-5p, alleviating its suppression of IL-6 mRNA, and enhancing inflammatory responses in AC16 cardiomyocytes. Our findings elucidated a molecular mechanism linking COVID-19 mRNA vaccines to myocarditis and highlighted the ceRNA-mediated crosstalk between IVT mRNA and IL-6. These results underscore the importance of avoiding critical microRNA binding sites in the design of next-generation mRNA vaccine sequences to improve safety.
Keywords: covid-19 mRNA vaccines, in vitro transcription mRNA, IL-6, ceRNA, Myocarditis
Received: 28 Jul 2025; Accepted: 10 Oct 2025.
Copyright: © 2025 Ge, Wang, Sun, Gao, Fu, Xiao and Du. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xi-yuan Ge, gexiyuan@bjmu.edu.cn
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