The main protease (Mpro) of SARS-CoV-2 plays a pivotal role in viral replication and immune evasion. Accumulating evidence highlights its significant role in suppressing innate immunity. In this review, we provide a comprehensive overview of how Mpro modulates host innate immune responses, including its interference with retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathways, inhibition of interferon production, and disruption of inflammasome activities. As a protease, Mpro cleaves a variety of host proteins to attenuate antiviral innate immunity, a process dependent on its catalytic dyad (Cys145-His41), which is crucial for its proteolytic activity. Meanwhile, Mpro also exerts innate immune regulatory functions in a protease-independent manner. Notably, inhibitors targeting Mpro have demonstrated efficacy in restoring immune functions and suppressing viral replication, offering potential therapeutic strategies against SARS-CoV-2 infection.

SARS-CoV-2  /  Main protease  /  Innate immunity  /  Type I IFN  /  Inhibitor