{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTsukushi (TSK), a small leucine‐rich repeat proteoglycan, functions as a versatile extracellular regulator that modulates multiple signaling pathways involved in tissue development and homeostasis. In developmental settings, TSK is expressed in a restricted pattern in the hair follicle, where it directly binds transforming growth factor–β1 to regulate TGF‑β signaling and thereby control the normal cycling of hair growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, mesenchymal expression profiling in the developing prostate has revealed that reduced expression of TSKU in the stroma may be associated with malignant transformation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", and broader reviews have highlighted its role in coordinating extracellular signals during growth, wound healing, and cartilage formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn metabolic disease contexts, TSK acts as a hepatokine produced in response to liver stress and nonalcoholic fatty liver disease (NAFLD). Its upregulation is driven by endoplasmic reticulum stress and inflammation, and increased circulating levels are linked to dysregulated cholesterol homeostasis – with effects such as reduced HDL cholesterol, diminished cholesterol efflux capacity, and impaired cholesterol-to–bile acid conversion – thereby potentially connecting liver pathology with atherogenic dyslipidemia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, clinical studies have demonstrated that serum TSK concentrations are elevated in hyperthyroid patients and correlate with thyroid hormone levels and basal metabolic rate"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while weight loss induced by bariatric procedures leads to a marked reduction in hepatic TSK expression, suggesting its utility as a biomarker of metabolic improvement and NAFLD severity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the oncologic arena, TSKU has emerged as a functionally significant target in neuroblastoma, where its knockdown is associated with enhanced cell differentiation and decreased cell survival – findings that correlate with patient prognosis, as high TSKU mRNA levels portend poor survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Similarly, its expression is under investigation in lung cancer, where TSK’s role in modulating cell signaling may implicate it in tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daisuke Niimori, Rie Kawano, Athary Felemban, et al. 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