Epigenetic and Molecular Regulation of the IL-6 Axis in COVID-19: A Narrative Review of the Most Important microRNA-Mediated Mechanisms Involved in Cytokine Storm and Therapeutic Perspectives

Abstract

Context: The COVID-19 pandemic, caused by SARS-CoV-2, is characterized by a severe hyperinflammatory response driven by a cytokine storm, in which interleukin-6 (IL-6) plays a central pathogenic role. This review examines the epigenetic regulation of the IL-6 axis by microRNAs (miRNAs) in the pathophysiology of COVID-19. Evidence Acquisition: This review examines evidence on specific miRNAs involved in the regulation of IL-6 signaling, including miR-155, miR-451a, miR-98 - 5p, miR-146a, miR-106a, and miR-20a, with particular attention to their effects on the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) pathways. Systems biology approaches were also considered to identify key miRNA regulatory hubs within the inflammatory network. Results: In severe COVID-19, miR-155 amplifies inflammation by repressing negative regulators such as SOCS1, whereas downregulation of miR-451a leads to IL-6 receptor overexpression and increased inflammatory sensitivity. In contrast, protective miRNAs such as miR-146a act as molecular brakes against excessive innate immune responses. Reduced levels of miR-98 - 5p, miR-106a, and miR-20a are associated with poor clinical outcomes and increased mortality. These miRNAs have been identified as key regulatory hubs within highly interconnected inflammatory networks. Their stability in biofluids also makes them promising noninvasive biomarkers for early diagnosis, prognostication, and monitoring of disease severity. Conclusions: miRNAs involved in the IL-6 signaling axis may serve as valuable biomarkers and therapeutic targets in COVID-19. Emerging approaches, including miRNA mimics and antagomiRs, may help restore immune homeostasis and mitigate the IL-6-driven cytokine storm. Longitudinal studies are needed to translate these epigenetic findings into routine clinical practice and support the precision management of COVID-19 and its long-term sequelae.