MFAP5 (microfibril-associated protein 5) is a component of elastin-associated microfibrils that plays critical roles in extracellular matrix organization and fibroblast biology across multiple disease contexts. In healthy tissue, MFAP5 identifies a major fibroblast population in the lung and is a key driver gene for fascia fibroblast differentiation during skin development 12. MFAP5 functions primarily through regulation of cancer-associated fibroblasts (CAFs) in the tumor microenvironment. In pancreatic cancer, MFAP5-high CAFs promote immunosuppression via the MFAP5/RCN2/ERK/STAT1 axis, reducing hyaluronic acid deposition and CXCL10 expression, while MFAP5 inhibition sensitizes tumors to immunochemotherapy 3. Similarly, in gastric cancer, MFAP5+ CAFs exhibit pro-metastatic properties through NOTCH1/HEY1 signaling and are selectively enriched in peritoneal metastases, correlating with poor prognosis and immunosuppressive microenvironments with reduced natural killer cells and increased M2 macrophages 45. Beyond cancer, MFAP5 contributes to calcific aortic valve disease pathogenesis in diabetic patients 6 and varicose vein disease through epigenetic upregulation via active demethylation 7. MFAP5 has also been identified as a potential target through which personal care product chemicals associate with osteoarthritis 8. These findings establish MFAP5 as a multifunctional stromal regulator with significant clinical implications for cancer immunotherapy and vascular/connective tissue disorders.