The Dual Role and Therapeutic Implications of the Wnt/β-Catenin Pathway in Diabetic Kidney Disease

Yilinuer Adeerjiang,1,2 Xiao-Xue Gan,1,2 Wen-Ting Li,3 Qin-Tian Li,3 Yi-Qi Jiang,3 Xia Zhu,3 Chen-Ming Hu,3 Pan-Xia Wang,4 Sheng Jiang1,2 1Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 2State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, People’s Republic of China; 3First Clinical Medical College of Xinjiang Medical University, Urumqi, People’s Republic of China; 4Department of Endocrinology, People’s Hospital of Kashgar, Kashgar, People’s Republic of ChinaCorrespondence: Pan-Xia Wang, Department of Endocrinology, People’s Hospital of Kashgar, Kashgar, People’s Republic of China, Email [email protected] Sheng Jiang, Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China, Email [email protected]: Diabetic kidney disease (DKD), a major microvascular complication of diabetes, affects 30– 40% of patients and is the leading cause of end-stage renal disease. The Wnt/β-catenin signaling pathway plays a dual role in DKD pathogenesis: its moderate activation protects against hyperglycemia-induced mesangial apoptosis, while chronic overactivation exacerbates renal fibrosis, podocyte injury, and tubular dysfunction. This review synthesizes current evidence on the pathway’s context-dependent mechanisms. Emerging therapeutic strategies—including small-molecule inhibitors (eg, Dickkopf-1), monoclonal antibodies, and natural compounds like curcumin and Salvia miltiorrhiza extracts—show preclinical promise in modulating Wnt/β-catenin activity. However, clinical translation faces challenges such as pathway redundancy, off-target effects, and the need for precise dosing to balance protective and injurious outcomes. Recent advances in biomarker discovery (eg, urinary β-catenin) and ongoing clinical trials highlight the pathway’s potential as a therapeutic target. Future research must prioritize patient stratification, combination therapies (eg, Wnt inhibitors + RAAS blockers), and mechanistic studies to address unresolved controversies in Wnt signaling dynamics. This work underscores the therapeutic implications of targeting Wnt/β-catenin in DKD while advocating for a nuanced approach to harness its protective roles.Keywords: Wnt/β-catenin pathway, diabetic kidney disease, therapy