The Regnase pathway: a core axis in immune regulation and inflammatory disease

The Regnase/MCPIP ribonucleases are involved in the regulation of immune homeostasis, by degrading RNA transcripts that encode inflammatory and regulatory proteins. This review highlights their molecular architecture, catalytic mechanisms, and intricate regulatory networks that orchestrate innate and adaptive immunity. This article presents a narrative review of the literature on distinct physiological roles of individual family members and how their dysfunction drives inflammatory, autoimmune, fibrotic, metabolic, and neoplastic disorders across multiple tissues. Although Regnase family members exhibit some functional redundancy, each also possesses distinct, non-overlapping roles. Regnase-1 restrains cytokine production and along with Regnase-2 modulates neuroinflammation. Both Regnase-3 and Regnase-4 possess homeostatic functions although they are also involved in orchestrating interferon and myeloid signaling and contribute to immune regulation and tumor suppression. We also examine emerging therapeutic strategies targeting Regnase activity, including antisense oligonucleotides to enhance Regnase-1 expression, gene- and RNA-based delivery approaches, and selective inhibition of Regnase-1 in T cells to boost cancer immunotherapy. Together, these findings underscore Regnase proteins as central post-transcriptional checkpoints in immunity and highlight their potential as targets for treating autoimmune disease, chronic inflammation, fibrosis, and cancer.