CMTM5 (CKLF-like MARVEL transmembrane domain containing 5) is a membrane-associated protein with tumor suppressor properties involved in regulating cell adhesion, migration, and proliferation. As a member of the MARVEL domain-containing family 1, CMTM5 functions through protein-protein interactions to modulate critical cellular signaling pathways. Mechanistically, CMTM5 inhibits cancer cell growth by suppressing the PI3K/AKT signaling pathway 23. In prostate cancer, CMTM5 overexpression downregulates EGFR expression and downstream PI3K/AKT signaling, reducing Bcl-2 expression while increasing pro-apoptotic Bax, thereby promoting cell apoptosis 3. In cardiovascular disease, CMTM5 overexpression paradoxically inhibits vascular endothelial cell proliferation and migration through PI3K/Akt pathway regulation 4, yet elevated CMTM5 promotes monocyte adhesion and migration, contributing to atherosclerosis pathogenesis 5. Clinically, CMTM5 is significantly downregulated across multiple cancer types. In prostate cancer, reduced expression correlates with higher Gleason scores 26 and inverse EGFR upregulation 6. In breast cancer, decreased CMTM5 expression associates with worse relapse-free survival 1. CMTM5 variants (rs723840) correlate with high on-aspirin platelet reactivity and in-stent restenosis risk in coronary artery disease patients 74. Additionally, CMTM5 expression is reduced in vascular dementia 8, suggesting broader neuroprotective roles requiring further investigation.