Non-coding RNAs: master regulators in the battle between host antiviral defense and viral replication.

Viral infectious diseases pose serious threats to global public health. Host non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, circRNAs, and vtRNAs, act as master regulators of host antiviral defense and viral replication. Current studies on ncRNA-virus interactions are generally fragmented, and most reviews focus on a single virus or a single class of ncRNAs, without combining ncRNA expression dynamics with their biological functions for systematic collation. Herein, we establish a novel four-category classification framework based on ncRNA expression patterns and functional characteristics upon viral infection. To counteract viral infections, the host dynamically modulates the expression of distinct ncRNAs to target proviral host factors, host restriction factors, other ncRNAs, micropeptides, and lipids, thereby orchestrating antiviral innate immune signaling pathways, viral replication cycles, autophagy, apoptosis, metabolic reprogramming, and stress granule formation to establish a multilayered antiviral defense system. Concurrently, representative viruses posing severe threats to global public health, including IAV, DENV, HCV, ZIKV, HIV-1, and SARS-CoV-2, have evolved sophisticated strategies to hijack host ncRNA networks and antagonize host antiviral defenses. This review systematically summarizes and elaborates the conserved regulatory principles of various ncRNAs in the host antiviral response, clarifies the molecular mechanisms by which viruses hijack and antagonize host ncRNAs, further refines the theoretical framework of host ncRNA-virus interactions centered on viral replication regulation, discusses the future research directions under this system, and thus provides a theoretical basis for the development of host ncRNA-based antiviral drugs.