{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Follistatin‐like 3 (FSTL3), also known as follistatin‐related gene (FLRG), is a secreted glycoprotein that acts as a key extracellular antagonist of several transforming growth factor–β superfamily ligands, including activin and myostatin."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Structural and biochemical studies demonstrate that FSTL3 directly binds mature myostatin and activin, thereby inhibiting downstream signaling pathways such as those mediated by Smad proteins. In skeletal muscle, FSTL3 contributes to the tight regulation of myostatin bioactivity and is modulated by resistance exercise, suggesting a role in muscle growth and regeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond muscle, FSTL3 plays important roles in metabolic homeostasis. Its mRNA levels are differentially regulated in adipose tissue during obesity—with increased expression in subcutaneous fat—and genetic ablation of FSTL3 in mice results in increased pancreatic islet size, beta‐cell hyperplasia, decreased visceral fat mass, improved glucose tolerance, and enhanced insulin sensitivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cardiovascular system, FSTL3 modulates activin A signaling under stress conditions. In cultured cardiomyocytes and in vivo models of myocardial injury or pressure overload, FSTL3 influences Smad phosphorylation and hypertrophic responses; notably, cardiomyocyte‐specific deletion of FSTL3 attenuates pathologic cardiac hypertrophy and improves functional outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Differential cell‐surface binding compared to follistatin endows FSTL3 with unique ligand specificity, a feature that is implicated in reproductive development and tumor biology. In gonadal tissues, FSTL3 appears to regulate local activin action with consequences for gametogenesis, while in breast cancer elevated FSTL3 expression is associated with enhanced tumor cell proliferation by antagonizing activin’s antiproliferative effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, increased FSTL3 expression in placental tissues has been observed in intrauterine growth restriction, suggesting an important role in regulating fetal growth and differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Overall, FSTL3 serves as a context‐dependent modulator of TGF–β family signaling with broad implications for muscle physiology, metabolic control, cardiac remodeling, reproductive development, and cancer progression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jennifer J Hill, Monique V Davies, Adele A Pearson, et al. 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