RHBDF2 encodes iRHOM2, a catalytically inactive rhomboid superfamily member that serves as a critical regulator of ADAM17 metalloproteinase activity 1. The protein functions as a non-catalytic subunit that binds to ADAM17 and modulates its proteolytic cleavage of cytokines including tumor necrosis factor and amphiregulin 12. Loss-of-function mutations in RHBDF2 cause immunodeficiency with recurrent infections due to defective ADAM17-dependent cytokine release 1. In neuroinflammation, RHBDF2 promotes microglial activation through interaction with STING and activation of the STING-TBK1-IRF3/p65 signaling pathway 3. The protein also modifies TREM2 proteolysis in microglia, where iRHOM2 loss increases surface TREM2 levels and enhances microglial phagocytosis of amyloid β-peptide 2. RHBDF2 expression is upregulated in various cancers including hepatocellular carcinoma, where it correlates with poor prognosis and immune infiltration 45. In metabolic disease, RHBDF2 promotes non-alcoholic fatty liver disease progression and is negatively regulated by the E3 ubiquitin ligase TRIM31 6. The protein's expression is post-transcriptionally regulated by m6A methylation through the YTHDF1 reader 3.