Highland barley polyphenols mitigate cisplatin-induced nephrotoxicity via mitochondrial protection and metabolic reprogramming.

Cisplatin (DDP)-induced acute kidney injury (AKI) presents a major challenge in chemotherapy, limiting its clinical utility due to nephrotoxicity. In this study, we explored the therapeutic potential of polyphenol-rich extracts from highland barley (HBPE) in counteracting DDP-induced renal damage. We hypothesized that HBPE could exert protective effects through the modulation of oxidative stress, mitochondrial dysfunction, and metabolic dysregulation. Using UHPLC-QTOF/MS-based untargeted metabolomics, we identified key metabolic disruptions in human embryonic kidney (HEK293) cells treated with DDP, which were substantially reversed by HBPE. The extract significantly attenuated mitochondrial injury and oxidative stress, as shown by decreased malondialdehyde (MDA) levels; increased levels of glutathione (GSH), superoxide dismutase (SOD), and ATP; and reduced reactive oxygen species (ROS) (P < 0.05). Furthermore, HBPE inhibited apoptosis by stabilizing mitochondrial integrity. In vivo, HBPE pretreatment ameliorated renal dysfunction in rats, as evidenced by reduced serum creatinine and blood urea nitrogen (BUN) levels and improved renal histopathology. Metabolomic profiling identified 39 potential biomarkers and revealed that HBPE restored key metabolic pathways, including folate biosynthesis, nicotinate metabolism, and phenylalanine metabolism. These results support the potential of HBPE as a natural nephroprotective intervention during chemotherapy. Derived from a sustainable agricultural source, HBPE offers a promising, low-toxicity strategy for enhancing patient safety and promoting integrative therapeutic development.