Morroniside alleviates cisplatin-induced renal injury and gut dysbiosis via the gut-kidney axis and ferroptosis.

BACKGROUND

The clinical use of cisplatin as a chemotherapeutic agent is limited owing to its nephrotoxicity. Oxidative stress and ferroptosis are responsible for cisplatin-induced renal injury.

PURPOSE

The protective effects of morroniside against cisplatin-induced renal injury were evaluated and its underlying molecular mechanisms were elucidated.

METHODS

An animal model of cisplatin-induced renal injury was established using male C57BL/6 mice. Renal function was assessed by measuring serum creatinine (CRE), uric acid (UA), and blood urea nitrogen (BUN) levels. Antioxidant enzyme activity and pro-inflammatory cytokine levels were determined, and histological studies of renal and colon tissues were performed. Western blotting and immunohistochemical analysis were performed to determine the expression of ferroptosis-related proteins and nuclear factor erythroid 2-related factor (Nrf)2 signaling pathway. Gut microbiota were analyzed using 16S rRNA sequencing. Cisplatin- or erastin-induced renal tubular epithelial cell (HK-2 cells) models were established. Intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential were measured. The expression of Nrf2, heme oxygenase 1 (HO-1), tumor protein 53 (p53) and glutathione peroxidase (GPX)4 proteins were determined using immunofluorescence.

RESULTS

Morroniside significantly ameliorated cisplatin-induced renal dysfunction, as evidenced by decreased serum CRE, UA, and BUN levels. It reduced pro-inflammatory cytokine levels, enhanced antioxidant enzyme levels, and improved renal and colon histology. Morroniside corrected gut dysbiosis, reduced ROS levels, increased mitochondrial membrane potential, and decreased HK-2 cell apoptosis, alleviating cisplatin- or erastin-induced oxidative stress and ferroptosis.

CONCLUSION

Morroniside mitigated cisplatin-induced renal injury by inhibiting ferroptosis through the GPX4/p53 pathway, reducing oxidative stress via Nrf2/HO-1 axis, and improving gut microbiota dysbiosis, indicating its potential in mitigating cisplatin-induced renal injury.