Endothelial PDGF Signaling Dysregulation Impairs Testicular Interstitial Homeostasis in Diabetes

The testicular interstitium relies on coordinated signaling among vascular, steroidogenic, and structural cells, yet the regulatory role of testicular endothelial cells (TECs) in maintaining this homeostasis remains unclear. Here, we identify TECs as a central signaling hub that orchestrates intercellular communication within the human testis. Integrative single-cell transcriptomic analysis of healthy and diabetic testes reveals that diabetes disrupts platelet-derived growth factor (PDGF) signaling. TECs in diabetes undergo endothelial-to-mesenchymal transition and exhibit reduced PDGFB expression, while Leydig and testicular peritubular cells downregulate PDGFRB, collectively weakening intercellular connectivity. This disruption silences the JUND-MCL1 survival program in Leydig cells, leading to apoptosis, extracellular matrix accumulation, and testosterone insufficiency, while impairing the contractility of testicular peritubular cells. Importantly, exogenous PDGF-BB supplementation reactivates the JUND-MCL1 axis, protects Leydig cells, alleviates fibrosis, and partially restores testosterone production and peritubular function. Together, these findings establish endothelial PDGF dysregulation as a key driver of diabetic testicular pathology and highlight PDGF-BB supplementation as a mechanistically grounded therapeutic strategy to restore interstitial and endocrine function in the context of diabetes.