SARS-CoV-2 reshapes m⁶A methylation in long non-coding RNAs of human lung cells

N⁶-Methyladenosine (m⁶A) is a key base modification that regulates RNA stability and translation during viral infection. While m⁶A methylation of host mRNAs has been studied in SARS-CoV-2-infected cells, its role in long non-coding RNAs (lncRNAs) is unknown. Here, we analyzed direct RNA sequencing (dRNA-seq) data from infected human lung cells (Calu-3) using a machine learning m⁶A detection framework. We observed a global increase in m⁶A levels across ten antiviral response–associated lncRNAs, with UCA1, GAS5, and NORAD—regulators of interferon (IFN) signaling—showing the most pronounced changes. This might, in part, explain the attenuated IFN expression observed in infected cells. We identified methylated DRACH motifs in predicted lncRNA duplex-forming regions, which may favor Hoogsteen base-pairing, which destabilize secondary structures and target interaction sites. These results provide new perspectives on how SARS-CoV-2 could impact lncRNAs to modulate host immunity and viral persistence through m⁶A-dependent mechanisms.