Chrysin mitigates ciprofloxacin-induced nephrotoxicity: associations with notch/HES1 signaling, inflammation, and a ferroptosis-related molecular signature.

Ciprofloxacin (CIP) is a widely used antibiotic frequently associated with dose-limiting nephrotoxicity. Chrysin (CHR), a natural flavonoid, possesses significant cytoprotective properties, yet its specific role in mitigating CIP-induced kidney injury remains underexplored. This study investigates the comprehensive nephroprotective mechanisms of CHR against CIP toxicity in rats. Male Wistar rats received CIP (100 mg/kg/day, i.p.) with or without CHR (50 mg/kg/day, p.o.) for 8 consecutive days. Results showed that CIP administration compromised renal function (urea, creatinine) and structural integrity, while markedly altering tubular injury markers (KIM-1, AQP-1). Biochemical and molecular analyses revealed that CIP disrupted cellular redox balance (MDA, GSH, SOD, CAT, GPx) and triggered a robust inflammatory response (NF-κB, TNF-α, IL-17A). Furthermore, CIP exposure engaged distinct cell death mechanisms, including intrinsic apoptosis (Bax, Bcl-2, Caspase-3) and ferroptosis (GPX4, TfR1, PTGS2). A novel finding was the activation of the Notch signaling pathway (Notch, HES1) in renal tissue. CHR co-treatment significantly attenuated these pathological changes, restoring renal function and histology, re-establishing antioxidant defenses, and suppressing inflammatory and apoptotic signaling and normalizing ferroptosis-related gene expression changes. In conclusion, CHR confers robust nephroprotection by targeting the inflammation-ferroptosis-apoptosis axis and modulating Notch signaling, positioning it as a promising adjuvant to mitigate CIP-induced renal injury.