Exploring the pharmacological mechanism of fermented Eucommia ulmoides leaf extract in the treatment of cisplatin-induced kidney injury in mice: Integrated traditional pharmacology, metabolomics and network pharmacology

Cisplatin (CP) is a widely utilized anticancer drug, which also produces significant side effects, notably acute kidney injury (AKI). Fermented Eucommia ulmoides leaf (FEUL), a medicinal and edible Chinese herbal remedy, is known for its renoprotective properties. However, the effect and underlying mechanism of FEUL extract in AKI therapy have remained largely unexplored. This research aimed to elucidate the protective roles of FEUL extract in an AKI mouse model through biochemical assays, histopathological examinations, and investigating the underlying mechanisms based on metabolomics and network pharmacology. The findings demonstrated that pretreatment with orally administered FEUL extract significantly reduced blood urea nitrogen (BUN), and serum creatinine (SCr) levels, and ameliorated CP-induced kidney histopathological injuries. Moreover, FEUL extract attenuated CP-induced endoplasmic reticulum (ER) stress by reducing the protein expressions of PERK, IRE 1α, GRP78, ATF6, ATF4, and CHOP. The metabolomics results indicated that a total of 31 metabolites, involved in taurine and hypotaurine metabolism, lysine degradation, and steroid hormone biosynthesis, were altered after FEUL extract administration. Furthermore, metabolomics integrated with network pharmacology revealed that 8 targets, 4 metabolites, and 3 key pathways including steroid hormone biosynthesis, purine metabolism, and tryptophan metabolism were the main mechanisms of FEUL extract in treating CP-induced AKI. These findings suggested that FEUL extract could offer valuable insights for potential CP-induced AKI treatment strategies.