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ABSTRACT The rhomboid superfamily, comprising both proteases and pseudoproteases, has emerged as a central regulator of membrane biology, mediating diverse functions including protein quality control, signal transduction, trafficking, and more. While molecular mechanisms of rhomboid activity have been well‐characterized in invertebrate and cell‐based systems, their physiological role in vertebrate development remains limited and continues to evolve. Here, we review recent advances in cell culture systems and vertebrate models that uncover the developmental and disease‐relevant functions of rhomboid family members, including RHBDLs, iRhoms, PARL, and Derlins. We outline their roles in embryogenesis, tissue regeneration, neurodevelopment, and immune signaling, alongside their pathological involvement in cancer, neurodegeneration, and metabolic disorders. We also emphasize the limitations posed by early embryonic lethality in knockout models and advocate for tissue‐specific vertebrate models to dissect rhomboid‐dependent pathways in vivo. Understanding how rhomboid proteins coordinate developmental processes will not only reveal fundamental principles of membrane‐associated processes, but also open new avenues for therapeutic targeting in disease. 

Abstract Tissue regeneration requires tight control of immune cell behavior, yet the mechanisms that restrain immune-driven regenerative responses remain poorly defined. Here, we identify the rhomboid intramembrane serine protease Rhbdl2 as a critical regulator of regeneration in zebrafish. We generatedrhbdl2mutants by CRISPR-Cas9 and found that it does not affect normal development, but triggers enhanced regenerative growth following injury, accompanied by increased macrophage accumulation at the wound site, which is accompanied by increased early apoptosis and proliferation. Proteomic analyses reveal increased Rac2 protein levels inrhbdl2mutants, indicating dysregulated immune signaling. Functionally, Rac2 morpholino oligonucleotides-mediated knockdown inrhbdl2mutant larvae suppresses the elevated macrophage recruitment and enhanced tissue regenerative phenotype. Together, these findings uncover Rhbdl2 as an immune checkpoint that constrains macrophage-driven enhanced regeneration, with vast implications for inflammatory disease, fibrosis, and tumor–immune interactions.