Rhbdf2, encoding the inactive rhomboid protease iRhom2, is a catalytically deficient member of the rhomboid protein family. It activates the MAP3K7-dependent pathway, and is involved in regulating the maturation of tumor necrosis factor-alpha (TNF-α) converting enzyme, which is responsible for the release of TNF-α [2,5]. Rhbdf2 has been implicated in various biological processes such as wound healing, and is associated with diseases like cancer, neurological disorders, and inflammation [2].

In mouse models, hepatocyte-specific Trim31 ablation, which targets Rhbdf2 for proteasomal degradation, facilitates NAFLD-associated phenotypes, while Trim31 gain-of-function alleviates steatohepatitis, suggesting Rhbdf2's role in non-alcoholic fatty liver disease (NAFLD) [1]. Loss of Rhbdf2 in Il10-/-mice leads to early-onset spontaneous colitis, correlating with dysbiotic gut microbiota and elevated Th1-associated immune responses [3]. Rhbdf2Pomc mice (proopiomelanocortin-specific Rhbdf2 deficiency) show mitigation of PM2.5-induced neurological injury and neuron loss [4]. Also, Rhbdf2 knockout mice have alleviated collagen-induced arthritis severity, indicating its role in TNF-α related diseases [5].

In conclusion, Rhbdf2 plays crucial roles in multiple biological processes and disease conditions. Mouse models, especially gene-knockout (KO) models, have been instrumental in revealing its functions in diseases such as NAFLD, colitis, neurological injury related to air pollution, and collagen-induced arthritis. These findings provide potential therapeutic targets for the treatment of associated diseases.