Beyond Immunity: RIG-I as a Bifunctional Regulator of Cell Fate in Non-Infectious Diseases

Retinoic acid-inducible gene (RIG-I) is highly regarded for recognizing short-stranded RNA with a triphosphate motif at the 5′ end to participate in the antiviral innate immune response. Recent studies have demonstrated that RIG-I expression remains upregulated during the terminal phase of RNA virus infection, persisting even after interferon production has terminated. Furthermore, studies have demonstrated the up-regulation or activation of RIG-I expression in non-viral disease contexts, implying a potential non-immune role for RIG-I. RIG-I possesses multiple structural domains, including Cards, Helicase, and CTD, which confer functional versatility in response to diverse stimuli. These domains enable RIG-I to participate in various biological processes beyond viral immunity, such as programmed cell death (PCD), tumor immunity, and cell proliferation. This review focuses on the role of RIG-I in regulating PCD, encompassing apoptosis, immunogenic cell death, necroptosis, pyroptosis, and autophagy. We systematically analyze the molecular mechanisms by which RIG-I modulates these PCD pathways and discuss the therapeutic potential of RIG-I-targeting activators and antagonists. These advances provide critical insights for developing novel treatments for diseases linked to RIG-I dysregulation.