Rhbdf2, also known as rhomboid 5 homolog 2 or iRhom2, encodes an inactive rhomboid protease. It is involved in multiple pathways, such as regulating 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 has been implicated in various biological processes and diseases, including wound healing, cancer, neurological disorders, inflammation, and skin diseases [2]. Gene-targeted mouse models have been valuable in studying its functions [5].

In mouse models, hepatocyte-specific Trim31 ablation, which normally binds to Rhbdf2 and facilitates its proteasomal degradation, leads to NAFLD-associated phenotypes, while Trim31 gain-of-function alleviates steatohepatitis, suggesting Rhbdf2 may be involved in the pathogenesis of NAFLD/NASH [1]. Il10 -/- /Rhbdf2 -/- mice develop spontaneous colitis, indicating a role for Rhbdf2 in maintaining the homeostasis between intestinal microbiota and host immune responses in the gut during IBD pathogenesis [3]. Rhbdf2-deficient mice also show alleviation of collagen-induced arthritis, a TNF-α related disease [5]. In addition, in PM2.5-exposed mice, proopiomelanocortin-specific Rhbdf2 deficiency mitigates neurological injury and neuron loss [4].

In conclusion, Rhbdf2 is a key regulator in multiple biological processes. Studies using gene-knockout mouse models have revealed its importance in diseases like non-alcoholic fatty liver disease, inflammatory bowel disease, collagen-induced arthritis, and neurological diseases related to PM2.5 exposure. These findings provide potential therapeutic targets for treating related disorders.