FSTL1

is a secreted glycoprotein belonging to the family of secreted protein acidic and rich in cysteine (SPARC) PMID 40588098. It is a multifunctional protein that acts as a pleiotropic regulator across several anatomical systems PMID 40588098.

• Cardiovascular Homeostasis: FSTL1 exerts cardioprotective, pro-angiogenic, and regenerative effects, contributing to stress adaptation in the heart PMID 40588098. It helps optimize endothelial integrity and vascular tone PMID 40588098.
• Skeletal Development: It is a critical mediator of osteochondral development and remodeling, promoting the production of chondrocytes and bone reconstruction PMID 40588098.
• Immunomodulation: It regulates innate and adaptive immune responses, specifically by influencing macrophage polarization and the activation of T lymphocytes PMID 40588098.
• Metabolic Regulation: FSTL1 plays a role in glucose metabolism and insulin sensitivity, particularly in the context of obesity and type 2 diabetes PMID 38786764PMID 40588098.

FSTL1 is considered an exerkine because its expression and secretion are dynamically regulated by physical activity PMID 40588098:

• Response to Modality: Sustained endurance training induces significant elevations in circulating FSTL1 PMID 40588098. Additionally, mechanical stress from resistance exercise stimulates the expression of skeletal muscle-derived FSTL1 PMID 40588098PMID 40210118.
• Release Mechanism: It is synthesized and released from skeletal muscle (as a myokine) and cardiac tissue (as a cardiokine) into the circulation in response to acute and chronic exercise stimuli PMID 38107476PMID 40210118.
• Correlation with Fitness: Its circulating levels positively correlate with lean mass indices and lipid mobilization markers PMID 40588098.

• Cardiac Repair and Protection: FSTL1 mediates exercise-induced cardioprotection after myocardial infarction (MI). It mitigates pathological cardiac remodeling, reduces myocardial fibrosis, and improves heart function PMID 40210118PMID 40588098.
• Angiogenesis: It enhances coronary angiogenesis and revascularization in ischemic tissues, primarily by binding to the DIP2A receptor and activating Smad2/3 signaling PMID 40210118PMID 40588098.
• Neuroprotection: In models of ischemic stroke, FSTL1 has been shown to reduce infarct volume and promote functional recovery through the activation of DIP2A/Akt signaling PMID 40818821.
• Metabolic Disorders: It is highlighted for its potential to improve glycemic control and insulin sensitivity PMID 40588098.
• Duality in Joint Disease: While it has regenerative potential, FSTL1 can also act as a pro-inflammatory factor in the pathogenesis of osteoarthritis, where it correlates with joint damage severity. Consequently, it is being investigated both as a biomarker for disease severity and a potential target for therapeutic management PMID 38107476

Cardiovascular Disease: FSTL1 shows cardioprotective effects in myocardial infarction. Administration of FSTL1 protein significantly reduced infarct size in both mouse and pig models of ischemia/reperfusion injury by inhibiting apoptosis and inflammatory responses through AMP-activated protein kinase and bone morphogenetic protein-4 pathways PMID 22929303. FSTL1 orchestrates post-infarction healing through multiple signaling cascades including BMP/SMAD, PI3K/AKT, MAPK, and TGF-β pathways, coordinating inflammation resolution, extracellular matrix remodeling, and functional recovery PMID 41602834, Additionally, FSTL1 protects against hypoxia-induced pulmonary hypertension by suppressing pulmonary artery smooth muscle cell proliferation and migration via the ERK signaling pathway PMID 28361925.

Fibrotic Diseases: Epitope-specific monoclonal neutralizing antibodies targeting FSTL1 demonstrated potent antifibrotic effects in preclinical models. FSTL1 neutralizing antibodies attenuated bleomycin-induced pulmonary and dermal fibrosis, reduced TGF-β1-induced dermal fibrosis in human skin ex vivo, and significantly reduced existing lung and skin fibrosis PMID 33007201. These antibodies exerted their effects by reducing TGF-β1 responsiveness and subsequent myofibroblast activation PMID 33007201.

Inflammatory and Autoimmune Diseases: FSTL1 neutralizing antibodies attenuated collagen-induced arthritis severity in mice with reduced inflammatory responses PMID 33007201. However, FSTL1's role in inflammation appears context-dependent, as it has been identified as a proinflammatory protein that enhances synthesis of proinflammatory cytokines and chemokines PMID 24838142.

Renal Disease: FSTL1 plays a role in kidney pathology, particularly in renal fibrosis, inflammation, and ischemia-reperfusion injury, suggesting potential as both a biomarker and therapeutic target PMID 40239460.