FSTL3 (follistatin-like 3) is a secreted antagonist of TGF-β superfamily ligands, particularly activins and BMPs, functioning as a key regulator of multiple physiological systems. The protein inhibits activin A and B-induced signaling 1 and negatively regulates bone formation by inhibiting osteoclast differentiation. In hematopoiesis, FSTL3 promotes hematopoietic progenitor cell adhesion to bone marrow stroma. FSTL3 also exists as a nuclear isoform involved in transcriptional regulation. Clinically, circulating FSTL3 emerges as a prognostic biomarker across multiple conditions. In pulmonary arterial hypertension, baseline and follow-up serum FSTL3 levels independently predict transplant-free survival, with threshold values of 16.6 ng/mL identifying high-risk patients 2. Similarly, FSTL3 is a senescence-associated protein causally linked to heart failure development 3 and correlates with aging, frailty, and cardiac dysfunction 4. The protein partially mediates increased acute myocardial infarction risk in diabetic patients with liver fibrosis 5 and contributes to dementia risk associated with poor cardiovascular health 6. In pregnancy, elevated FSTL3 predicts preeclampsia and fetal growth restriction 7. Therapeutically, FSTL3 neutralization enhances glucose-responsive insulin secretion in dysfunctional pancreatic islets 1 and improves glucose metabolism by releasing Activin B-mediated metabolic benefits 8, suggesting FSTL3 inhibition as a potential diabetes treatment strategy.