Interferon regulatory factors: the next prospective targets for tissue ischemia–reperfusion injury?

Ischemia-reperfusion injury (IRI) represents a severe form of tissue or organ damage that occurs spontaneously and passively during the reperfusion process, following abrupt pathophysiological disturbances in the internal milieu. Alleviating and preventing IRI during organ resection or transplantation has long been a prevalent and intricate challenge in this field. Interferon regulatory factors (IRFs) constitute a superfamily of transcription factors that play pivotal roles in regulating diverse cellular biological functions, encompassing immune response modulation, inflammatory reaction control, cell proliferation and differentiation, and antiviral defense. The activation of IRFs and their downstream gene regulation primarily depend upon signal stimulation by three types of interferons (IFNs), forming an IFN-IRF-target gene cascade pathway. Consequently, the expression functions induced by IRFs under each IFN stimulus can exhibit markedly distinct characteristics. Recent studies have demonstrated that biological events involving IRFs are widespread across the cardiovascular system, central nervous system, and organs including the kidneys, liver, and intestine. Intervention targeting IRFs and their associated pathways has emerged as a significant research direction for preventing organ IRI. Nevertheless, the underlying regulatory mechanisms require further investigation and elucidation. This review aims to systematically expound the regulatory mechanisms and research advances concerning interferon regulatory factors (IRFs) and their related pathways in IRI across multiple systems and organs, from pathophysiological and molecular biological perspectives. This work not only illuminates the molecular basis of functional heterogeneity among IRFs but also proposes two innovative theoretical frameworks: the "dynamic regulatory network" and the "organ-IRF axis". Future research ought to integrate single-cell sequencing, organoid models, and artificial intelligence prediction to elucidate the dynamic regulatory network of IRFs, thereby addressing the challenges of translational bottlenecks. Furthermore, the development of organ-specific delivery systems and heightened attention to the roles of IRFs in novel cell death mechanisms will furnish crucial support for translating research findings in this domain into clinical practice.