The role of SARS-CoV-2 main protease in innate immune regulation: From molecular mechanisms to therapeutic implications

The main protease (M^pro) 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 M^pro 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, M^pro 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, M^pro also exerts innate immune regulatory functions in a protease-independent manner. Notably, inhibitors targeting M^pro have demonstrated efficacy in restoring immune functions and suppressing viral replication, offering potential therapeutic strategies against SARS-CoV-2 infection.