{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nIsthmin‐1 (ISM1) is a multifunctional secreted protein that has emerged as a key regulator of metabolic homeostasis and angiogenesis. Notably, ISM1 acts as an adipokine to enhance glucose uptake in adipose tissue and suppress hepatic lipid synthesis, thereby mitigating hyperglycemia and fatty liver disease, while simultaneously exerting anti‐angiogenic effects by inhibiting endothelial capillary network formation via its AMOP domain and integrin interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond metabolic regulation, ISM1 plays important roles in immune modulation and pulmonary homeostasis. It is expressed in selected lymphocyte subsets and upregulated upon T cell activation and Th17 polarization, suggesting a contributory role in both innate and adaptive immune responses. In the lung, ISM1 functions as an endogenous anti‐inflammatory protein by selectively triggering the apoptosis of proinflammatory alveolar macrophages that display high levels of cell‐surface GRP78, thereby protecting against emphysema and preserving lung function in chronic obstructive pulmonary disease. Moreover, ISM1 modulates pulmonary vascular permeability under stress conditions; alveolar epithelial cell–derived ISM1 is upregulated via HIF‐1α in hypoxia and through C/EBPβ during sepsis, actions that contribute to endothelial hyperpermeability as well as pulmonary vascular leakage, while decreased levels of ISM1 are linked to allergic airway inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDuring development and in tissue homeostasis, ISM1 displays dynamic spatiotemporal expression patterns across embryonic mesodermal and neural structures, indicating roles in early organ patterning. In the developing kidney, ISM1 promotes ureteric bud bifurcation and metanephric mesenchyme condensation by engaging integrin α8β1 and facilitating Gdnf/Ret signaling, while in skeletal muscle it distinctively activates the PI3K‐Akt and mTOR pathways to enhance protein synthesis and maintain proteostasis under metabolic stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zewen Jiang, Meng Zhao, Laetitia Voilquin, et al. 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