{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cellular repressor of E1A‐stimulated genes 1 (CREG1) is a multifunctional glycoprotein that plays a critical role in maintaining tissue homeostasis by coordinating cellular differentiation, proliferation, survival, and remodeling across diverse biological systems. In vascular smooth muscle cells, CREG1 promotes a quiescent, contractile phenotype and inhibits proliferation and migration by modulating IGF‐II trafficking and suppressing MAPK and PI3K/AKT signaling pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the heart, CREG1 exerts cardioprotective effects by attenuating hypertrophy, fibrosis, and ischemia/reperfusion injury—mechanisms attributed in part to enhanced lysosomal autophagy and inhibition of MAPK cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Intracellularly, CREG1 undergoes N‐glycosylation and lysosomal processing via its interaction with the mannose 6‐phosphate/IGF2 receptor, modifications that are crucial for its growth‐suppressive and differentiation‐promoting activities."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In endothelial cells, CREG1 reinforces cellular integrity by enhancing proliferation, survival, and angiogenic capacity through activation of the ERK/cyclin E, ILK–Cdc42, and VEGF/PI3K/AKT pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "15"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n During cardiac development, CREG1 is highly expressed and is essential for cardiomyocyte differentiation and myocardial cohesion. Its interaction with exocyst components such as Sec8 facilitates the assembly of adherens and gap junctions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " In parallel, CREG1 contributes to metabolic homeostasis by promoting brown adipocyte differentiation and upregulation of uncoupling protein 1, with reduced CREG1 predisposing to obesity and insulin resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "20"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, CREG1 mitigates pathological vascular remodeling by regulating adventitial fibroblast phenotype and suppressing inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " It also modulates the phenotype of cardiac fibroblasts under stress"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "and functions as a downstream effector in oncogenic signaling in KRAS‐mutant lung cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " In addition, CREG1 promotes vasculogenesis by upregulating VEGF expression and activating the PI3K/Akt pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings underscore the multifaceted role of CREG1 as a homeostatic modulator that coordinates cellular differentiation, growth arrest, survival, and remodeling in the vasculature, heart, and metabolic tissues.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jie Wang, Cheng-Hui Yan, Yang Li, et al. 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