FRMD8 (FERM domain containing 8) is a multifunctional protein that stabilizes cell surface iRhom proteins and regulates diverse cellular processes with significant disease implications. At the molecular level, FRMD8 promotes the cell surface stability of iRhom1 and iRhom2, preventing their endolysosomal degradation 1. By acting on iRhoms, FRMD8 indirectly regulates ADAM17-mediated shedding of TNF-α and other growth factors. Beyond iRhom regulation, FRMD8 negatively regulates Wnt signaling and controls estrogen receptor alpha (ERα) stability through dual mechanisms: inhibiting ESR1 transcription via FOXO3A and blocking UBE3A-mediated ERα degradation 2. FRMD8 also suppresses cell-cycle progression by inhibiting CDK4 activation and stabilizing the retinoblastoma protein 3. Clinically, FRMD8 dysfunction associates with multiple pathologies. Rare variants in FRMD8 predict increased Alzheimer's disease and related dementia risk 4. Low FRMD8 expression confers tamoxifen resistance in ERα-positive breast cancer through reduced ERα levels 2, while FRMD8 loss promotes triple-negative breast cancer metastasis via enhanced tmTNF-α signaling 1. Additionally, FRMD8 variants associate with earlier amyotrophic lateral sclerosis onset 5, and FRMD8 expression is decreased during preeclampsia development 6. SARS-CoV-2 nucleocapsid protein suppresses interferon-β induction by dysregulating the LINC01002-miR-4324-FRMD8 axis 7. FRMD8's emerging role across neurodegenerative, cancer, and infectious disease contexts suggests therapeutic potential.