Rhbdf2, also known as rhomboid 5 homolog 2 or iRhom2, encodes an inactive rhomboid protease. It is involved in regulating multiple intracellular signaling pathways, such as the MAP3K7-dependent pathway, and is crucial for the maturation of tumor necrosis factor-alpha (TNF-α) converting enzyme, which is responsible for TNF-α release [2,5]. Rhbdf2 is associated with many biological processes and diseases, including wound healing, cancer, neurological disorders, and inflammation [2]. Mouse models have been valuable in uncovering its functions.

In NAFLD and NASH, Trim31, an E3 ubiquitin-protein ligase, binds to Rhbdf2 and facilitates its proteasomal degradation. Hepatocyte-specific Trim31 ablation exacerbates NAFLD-associated phenotypes in mice, while Trim31 gain-of-function alleviates steatohepatitis, suggesting Rhbdf2 promotes steatohepatitis pathogenesis [1]. In renal clear cell carcinoma, high levels of Rhbdf2 gene expression indicate poor prognosis. Silencing Rhbdf2 in cell lines reduces cell proliferation and migration, and although high Rhbdf2 correlates with increased lymphocyte infiltration, overexpressed Rhbdf2 inhibits infiltrated immune cell activity by sustaining PD-L1 protein level [3]. In a murine colitis model, Il10 -/- /Rhbdf2 -/- mice develop early-onset spontaneous colitis with a dysbiotic gut microbiota, elevated Th1-associated immune responses, and impaired epithelial cell homeostasis, demonstrating Rhbdf2's role in maintaining gut homeostasis [4].

In conclusion, Rhbdf2 is a key regulator in multiple biological processes and disease conditions. Mouse gene-knockout (KO) models, such as in the studies of NAFLD/NASH, renal clear cell carcinoma, and colitis, have revealed its role in disease pathogenesis, highlighting its potential as a therapeutic target in these disease areas.