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journal article·2026-05-22Open access

Renal IGFBP6 Interacts With THBS1 to Drive Renal Cellular Senescence and Fibrosis

Ju‐tao Yu, Chang‐geng Xu, Xiao‐wei Hu, Run‐run Shan, Jia‐nan Wang, Xiang‐yu Li, Yu‐qing Wang, Yu‐hang Dong, Shen‐Zhuo‐Fan Huang, Shuai Sun, Tian Zhao, Ya‐Xin Ru, Xiao‐yu Shen, Rui Hou, Jian‐min You, Fei Zhang, Chao Li, Jie Wei, Chao Hou, Zhi‐juan Wang, Dan‐feng Zhang, Juan Jin, Jia‐gen Wen, Yu‐jie Liu, Ming‐ming Liu, Xiao‐ming Meng, Wei Wang

Advanced Science
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Abstract

ABSTRACT Epithelial dedifferentiation and myofibroblast activation are critical drivers of chronic kidney disease (CKD) progression. Elevated levels of IGFBP6 have been linked to decreased renal function in CKD patients, but its precise role and underlying mechanisms remain unclear. In this study, we observed significantly increased IGFBP6 expression in the kidney tissues of both renal fibrosis patients and animal models. Global or tubule‐specific IGFBP6 knockout attenuated renal cellular senescence and fibrosis development in mice. In vitro, IGFBP6 deficiency preserved epithelial cell phenotype and inhibited fibroblast activation. Additionally, anti‐IGFBP6 treatment demonstrated promising therapeutic effects in alleviating renal cellular senescence and fibrosis. Mechanistically, IGFBP6, acting as an adaptor protein, could bind to thrombospondin 1 (THBS1) and prevent its ubiquitination‐mediated degradation, thereby activating the THBS1‐CD47 cellular pathway in epithelial cells, which contributed to renal cellular senescence and fibrosis. Notably, both genetic and neutralizing antibody‐mediated inhibition of IGFBP6 alleviated renal cellular senescence and fibrosis, suggesting that the IGFBP6/THBS1/CD47 axis represents a potential therapeutic target for chronic kidney injury.
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Research context

OpenAlex topics: Chronic Kidney Disease and Diabetes · Telomeres, Telomerase, and Senescence · TGF-β signaling in diseases

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province the Key Laboratory of Anti‐inflammatory of Immune Medicines Ministry of Education Anhui Institute of Innovative Drugs School of Pharmacy Anhui Medical University Hefei China

Department of Urology The Central Hospital of Wuhan Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China

Key Laboratory for Molecular Diagnosis of Hubei Province The Central Hospital of Wuhan Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China

Department of Clinical Pharmacy Anhui Provincial Children's Hospital Hefei China

State Key Laboratory of Pharmaceutical Biotechnology College of Life Sciences Nanjing University Nanjing China

Department of Urology The First Affiliated Hospital of Anhui Medical University Institute of Urology, and Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation Anhui Medical University Hefei China

School of Chinese Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong China

Department of Nephrology The Second Affiliated Hospital of Anhui Medical University Hefei Anhui China

Department of Pharmacology School of Basic Medical Sciences Key Laboratory of Anti‐Inflammatory and Immunopharmacology Ministry of Education Anhui Medical University Hefei China

Department of Obstetrics and Gynecology The First Affiliated Hospital of USTC University of Science and Technology of China Hefei Anhui China

Department of Urology The Fifth Affiliated Hospital of Anhui Medical University Fuyang China

Funding

National Natural Science Foundation of China

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