MEGF8 (multiple EGF-like domains 8) is a transmembrane protein that functions as a negative regulator of hedgehog signaling 1. The protein localizes to synapses and is required for proper synaptic growth and organization, with mutations causing motor coordination deficits and altered neurotransmission 2. MEGF8 acts as part of a membrane-spanning ubiquitin ligase complex (MMM complex) composed of MEGF8, MOSMO, and MGRN1, which regulates left-right body axis patterning and organ development by attenuating hedgehog signaling through ubiquitination and degradation of Smoothened 13. Biallelic MEGF8 mutations cause Carpenter syndrome 2 (CRPT2), an autosomal recessive condition characterized by craniosynostosis, polysyndactyly, cryptorchidism, and notably, laterality defects in nearly half of patients 4. The syndrome is associated with intellectual disabilities and psychiatric disorders, potentially through synaptic dysfunction 2. Beyond developmental roles, MEGF8 has emerged as relevant in adult pathologies. In osteoarthritis, MEGF8 mediates TGF-β hyperactivation through a complex with GDF8 and ACVR2B, promoting cartilage degradation 5. In endometriosis-associated ovarian cancer, MEGF8 acts as a key regulator promoting metabolic reprogramming, immune evasion, and poor prognosis 6. Additionally, MEGF8 mutations associate with improved progression-free survival in mismatch-repair-deficient gynecologic cancers treated with nivolumab 7.