{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTransforming growth factor‐β1 (TGF‑β1) plays an essential role in regulating development and maintaining tissue homeostasis. It is indispensable for the specification of central nervous system microglia and proper lung development, as highlighted by studies showing its requirement for a unique microglial gene‐expression signature and normal alveolar septation (a failure that is observed in Marfan syndrome models). TGF‑β1 also mediates bone remodeling by coupling bone resorption with subsequent formation, directs mesenchymal stem cell differentiation and chondrogenesis, and enables the terminal differentiation of fibroblasts into myofibroblasts—all fundamental processes that underscore its integrative role during organogenesis and tissue repair."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the immune system, TGF‑β1 is a master regulator that drives differentiation and functional polarization of lymphocytes. It helps orchestrate the generation of T helper 17 cells from naive precursors (often in concert with IL‑21 or IL‑6) while simultaneously promoting the expansion and suppressive activity of naturally occurring regulatory T cells. In addition, TGF‑β1 modulates key effector populations such as natural killer cells by down‐regulating activating receptors—mechanisms that together maintain immune homeostasis and prevent uncontrolled inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the tumor microenvironment, TGF‑β1 exerts pleiotropic and context‐dependent effects. Although it can act as a tumor suppressor in early lesion development, in advanced cancers it often promotes epithelial–mesenchymal transition (EMT), invasion, and metastasis. It achieves this by modulating noncoding RNAs (such as lncRNA‑ATB), miRNA networks, and transcription factor circuits (for example, by counteracting p63 in complexes with mutant p53 or by engaging ZEB/miR‑200 feedback loops). TGF‑β1 also contributes to the establishment of tumor‐promoting stroma by inducing carcinoma‐associated fibroblast differentiation and by impinging on multiple signal transduction pathways that favor cell motility and survival in cancers of diverse origins including hepatocellular, gastric, breast, and glioblastoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant activation of TGF‑β1 signaling is a key driver of fibrosis, vascular remodeling, and other chronic pathological states. In multiple organ systems—including the liver, kidneys, vasculature, and lungs—excessive TGF‑β1 activation leads to myofibroblast conversion, enhanced extracellular matrix deposition, and epithelial–mesenchymal transitions. Furthermore, cross talk with other pathways (such as Wnt signaling), and interactions with secreted regulatory proteins (for example, Klotho or periostin), fine‐tune the fibrotic response and contribute to vascular lesions such as neointimal formation in vein grafts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in development, immunity, and fibrosis, TGF‑β1 modulates stem cell properties and influences disease outcomes in several other contexts. In models of glioma and other cancers, TGF‑β1 contributes to cancer stem cell self‐renewal and resistance to therapy, while its signaling cascades are intricately regulated by Smad proteins and noncoding RNAs. In metabolic contexts, for example during adipogenic differentiation, TGF‑β receptor signaling is modulated by miR‑21, further illustrating the multifaceted regulatory network governed by TGF‑β1. Such complexity in its signaling—integrating cues from master transcription factors and diverse inhibitory feedback loops—marks TGF‑β1 as a promising therapeutic target in a wide range of clinical settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Oleg Butovsky, Mark P Jedrychowski, Craig S Moore, et al. 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