FSTL1 is a secreted glycoprotein that regulates multiple physiological processes including angiogenesis, immune responses, and cell differentiation. The protein promotes endothelial cell survival and migration through AKT-dependent signaling and activates diverse cellular responses by engaging surface receptors including DIP2A, TLR4, and BMP receptors. FSTL1 functions as a myokine secreted by skeletal muscle that improves vascular endothelial function 1, and mediates inter-organ metabolic communication between muscle and liver via IRF4-FSTL1-DIP2A/CD14 signaling in the setting of nonalcoholic steatohepatitis 2. FSTL1 displays context-dependent roles in cancer and fibrotic disease. In gastric cancer, CAF-derived FSTL1 impairs NK cell cytotoxic function by inducing ferroptosis through upregulation of NCOA4 via the DIP2A-P38 pathway; functional targeting with FSTL1-neutralizing antibody and deferoxamine restored NK cell activity 3. In hepatocellular carcinoma, FSTL1-expressing F5-CAFs colocalize with cancer cells of higher stemness and correlate with worse prognosis 4. Conversely, FSTL1 demonstrates protective effects in liver fibrosis, where renal tubular epithelial-derived FSTL1 inhibits NF-κB-mediated epithelial inflammation 5, and host FSTL1 enhances stem cell therapy efficacy by facilitating early recruitment of inflammatory macrophages via CD14/TLR4/NF-κB signaling 6. FSTL1 has emerged as a potential therapeutic target, with monoclonal antibodies under investigation 7.