The role of SARS-CoV-2 main protease in innate immune regulation: From molecular mechanisms to therapeutic implications.
10.1016/j.apsb.2025.07.001
- Author:
Yumeng GAO
1
;
Jun ZHANG
1
Author Information
1. Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing 100191, China.
- Publication Type:Review
- Keywords:
Inhibitor;
Innate immunity;
Main protease;
SARS-CoV-2;
Type I IFN
- From:
Acta Pharmaceutica Sinica B
2025;15(9):4497-4510
- CountryChina
- Language:English
-
Abstract:
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.
