Water-soluble anthocyanins from Vaccinium myrtillus L. alleviate diabetic kidney disease by targeting ALOX15-mediated...

Diabetic kidney disease (DKD) is a major diabetic complication with limited therapeutic options. Vaccinium myrtillus L. (bilberry) has a long history in European traditional medicine for treating microvascular disorders, inflammatory conditions, and urinary system ailments. As a traditional medicinal food rich in water-soluble anthocyanins, it has been reported to exert nephroprotective effects; however, its bioactive constituents and molecular mechanisms remain poorly defined.

This study aimed to investigate the renoprotective effects of a water-soluble anthocyanin-rich bilberry extract (VmE) in DKD, to identify its bioactive components, and to elucidate the underlying molecular mechanisms.

A high-fat diet/streptozotocin-induced DKD mouse model was employed. The chemical profile of VmE was characterized by LC-MS. Renal function, histopathology, and metabolomics were evaluated. Integrated network pharmacology, molecular docking, microscale thermophoresis (MST), and molecular dynamics (MD) simulations were conducted to identify and validate key molecular targets.

VmE dose-dependently improved renal function, ameliorated tubulointerstitial injury, and restored metabolic homeostasis. Delphinidin-3-O-glucoside (Dp3Glc) and cyanidin-3-O-glucoside (Cy3Glc) were identified as the major anthocyanins. Both MST and MD simulations confirmed that Dp3Glc and Cy3Glc directly bind to arachidonate 15-lipoxygenase (ALOX15). This interaction inhibited ALOX15-mediated lipid peroxidation, resulting in reduced malondialdehyde (MDA) accumulation and iron overload, as well as restored glutathione (GSH) homeostasis, thereby attenuating ferroptosis in renal tubular cells.

VmE through its major anthocyanins Dp3Glc and Cy3Glc, alleviates DKD by directly targeting ALOX15 and suppressing lipid peroxidation-driven ferroptosis. These findings establish a pharmacological basis for developing VmE as a standardized nutraceutical for DKD management, bridging traditional use with modern mechanistic evidence.