N6-methyladenosine as a potential epitranscriptomic immune rheostat during SARS-CoV-2 infection

Abstract

N6-methyladenosine (m6A), the most abundant internal RNA modification in eukaryotic cells, has emerged as a critical regulator of antiviral host defense. Increasing evidence indicates that m6A functions beyond conventional post-transcriptional regulation by dynamically coordinating the magnitude, timing, and duration of immune responses during viral infection. In SARS-CoV-2 infection, dysregulated antiviral immunity is characterized by delayed interferon activation together with sustained inflammatory responses, suggesting the existence of regulatory mechanisms that continuously calibrate immune signaling rather than simply switching it on or off. In this review, we propose the concept of m6A as a potential “epitranscriptomic immune rheostat,” representing a conceptual framework in which m6A may fine-tune antiviral immunity through coordinated regulation of RNA stability, translational efficiency, and transcript turnover. We summarize how m6A shapes multiple layers of innate immune responses, including pattern recognition receptor sensing, type I interferon signaling, inflammatory buffering, and immune resolution. We further discuss emerging evidence suggesting that SARS-CoV-2 infection is associated with dynamic modulation of the m6A regulatory machinery and viral RNA methylation landscapes, while emphasizing that many mechanistic insights remain to be experimentally validated in SARS-CoV-2 models. In addition, we highlight the interplay between m6A regulation and immunometabolic remodeling, while distinguishing direct SARS-CoV-2 evidence from findings derived from other viral systems or broader m6A biology. Selected comparisons with Influenza A virus are discussed as complementary evidence to explore potentially conserved principles of m6A-mediated immune regulation among RNA viruses rather than as direct evidence for SARS-CoV-2 infection. Finally, we discuss the therapeutic implications of targeting the m6A regulatory network to recalibrate immune responses with temporal and cellular precision, while noting that current m6A-targeting strategies remain at the preclinical proof-of-concept stage and require further evaluation regarding specificity, safety, and translational feasibility. Collectively, this review provides a hypothesis-driven conceptual framework for understanding how m6A integrates RNA fate control with antiviral immunity and immunopathology during SARS-CoV-2 infection.