The Role of Regnase-1 in Autoimmune Diseases - A Future Therapeutic Target for Clinical Use.

Regnase-1, encoded by ZC3H12A gene, is a multifunctional immune regulator that maintains immune homeostasis through its RNase activity. By controlling mRNA stability, microRNA maturation, and ubiquitin-dependent signaling, Regnase-1 fine-tunes inflammatory responses in both innate and adaptive immune cells. Accumulating evidence has demonstrated that dysregulation of Regnase-1 contributes to aberrant immune activation and the development of autoimmune diseases. In this review, we summarize recent advances in understanding the molecular mechanisms underlying Regnase-1 function, including RNase-mediated degradation of proinflammatory transcripts, suppression of microRNA (miRNA) biogenesis, and deubiquitination of key signaling intermediates such as TNF receptor-associated factor (TRAF) family proteins. We further discuss the multilayered regulation of Regnase-1 expression at transcriptional, post-transcriptional, and post-translational levels, highlighting how inflammatory cues dynamically modulate its activity. Importantly, Regnase-1 exerts cell type-specific functions among macrophages, neutrophils, T cells, B cells, and innate lymphoid cells, thereby modulating immune activation, differentiation, and effector responses. Recent studies have linked Regnase-1 to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, and type 1 diabetes (T1D), suggesting its potential as a candidate biomarker or therapeutic target in autoimmune disorders. Regnase-1 has been shown to serve as a key negative regulator of inflammatory signaling pathways, including IL-23/IL-17–driven responses implicated in autoimmune pathogenesis. Although available data are largely derived from experimental models and observational clinical studies, current findings collectively highlight Regnase-1 as an upstream regulator of several inflammatory signaling pathways already being targeted in clinical practice. Further understanding of the disease- and cell-specific roles of Regnase-1 may facilitate the identification of novel diagnostic markers and the development of therapeutic targeting of Regnase-1 to restrain inflammatory response in autoimmune diseases.