Salvianolic acid A as a novel functional food ingredient attenuates diabetic nephropathy via PEBP1-mediated ferroptosis regulation

• SalA is a potential novel functional food ingredient derived from Salvia miltiorrhiza Bunge (Danshen), a plant material approved for use in health foods by China's National Health Commission. • Hyperglycemia-induced ferroptosis disrupts the GFB in DN. • PEBP1 plays a critical role in mediating ferroptosis-related GFB damage under hyperglycemic conditions. • SalA reduces GFB injury by preventing PEBP1 dysregulation, modulating key iron trafficking proteins, and hence attenuating ferroptosis. • SalA mitigates GFB structural injury, improves glomerular filtration function, and decreases proteinuria, ultimately protecting against DN. The growing demand for bioactive food ingredients to support metabolic health necessitates scientifically validated functional components. This study evaluated salvianolic acid A (SalA), a stable bioactive compound from Salvia miltiorrhiza Bunge, for its potential as a functional food ingredient to manage diabetic nephropathy (DN) by targeting ferroptosis in the glomerular filtration barrier (GFB). In vitro assays using mesangial cells, glomerular endothelial cells, and podocytes, ex vivo analyses of isolated mouse glomeruli, and in vivo studies in diabetic KK-Ay mice were conducted. SalA administration significantly attenuated ferroptosis in GFB cells, as manifested by reduced intracellular iron accumulation, decreased lactate dehydrogenase (LDH) release, elevated glutathione (GSH) levels, suppressed lipid peroxidation, and normalized expression of ferroptosis-associated genes and proteins. Additionally, SalA administration preserved GFB ultrastructure, improved glomerular filtration function, and reduced proteinuria in diabetic KK-Ay mice. Mechanistic studies identified phosphatidylethanolamine-binding protein 1 (PEBP1) as a critical mediator of hyperglycemia-induced ferroptosis that contributes to GFB dysfunction. SalA demonstrated strong binding affinity to PEBP1, thereby preventing its dysregulation and the activation of downstream pathological pathways. Transcriptomic analysis and subsequent validation further revealed that SalA modulates key iron trafficking proteins to maintain iron homeostasis. Collectively, these findings establish a robust scientific basis for incorporating SalA into functional food formulations aimed at promoting metabolic and renal health. With demonstrated efficacy, dose-responsiveness, and regulatory alignment, SalA represents a promising ingredient for next-generation health foods targeting chronic metabolic conditions such as DN.