FSTL1 (follistatin-like 1) is a secreted glycoprotein functioning as a pleiotropic regulator across multiple physiological and pathological processes. Primarily, it promotes endothelial cell survival, migration, and differentiation through AKT-dependent signaling, while also supporting cardiac myocyte survival 1. FSTL1 is secreted by skeletal muscle as a myokine that improves vascular endothelial function 2 and mediates inter-organ crosstalk between muscle and liver through IRF4-FSTL1-DIP2A/CD14 signaling, contributing to NASH pathogenesis 3. Mechanistically, FSTL1 initiates signaling cascades by engaging surface receptors including DIP2A, TLR4, and BMP receptors. In liver fibrosis, macrophage-derived FSTL1 promotes M1 polarization and inflammation via direct PKM2 binding and nuclear translocation 4. FSTL1 also facilitates stem cell therapy efficacy by enhancing CD14/TLR4/NF-κB-mediated recruitment of inflammatory macrophages 5. In cancer contexts, FSTL1 exhibits contradictory roles. CAF-derived FSTL1 suppresses NK cell cytotoxicity through DIP2A-P38-mediated ferroptosis in gastric cancer 6, and correlates with cancer stemness in hepatocellular carcinoma 7. Additionally, FSTL1 inhibits LDL transcytosis across arterial endothelium, potentially affecting atherosclerosis development 8. FSTL1's dual nature in cancer progression—acting as both tumor enhancer and inhibitor depending on context—positions it as a promising therapeutic target 9.