Nephroprotective Role of Ichnocarpus frutescens Leaf Extract Against Cisplatin-Induced Renal Injury: Evidence from Rat and HK-2 Cell Models via Nrf2–HO-1–GPX4 Axis Modulation

Cisplatin is a widely prescribed chemotherapeutic drug, but its dose-dependent nephrotoxicity restricts therapeutic use and contributes substantially to treatment-related morbidity. The renal injury is mediated by oxidative stress, mitochondrial dysfunction, inflammation, apoptosis, and ferroptosis. Natural products with multi-target protective actions represent a promising approach to attenuate this toxicity. The present study evaluated the nephroprotective effect of aqueous leaf extract of Ichnocarpus frutescens (ALIF) in both in vivo and in vitro models of cisplatin-induced nephrotoxicity. In Wistar rats, nephrotoxicity was induced by cisplatin [7.5 mg/kg, intraperitoneal (i.p.) route] and treated with ALIF [100–400 mg/kg, orally (p.o.) (by mouth)] or hesperidin (100 mg/kg, p.o.) for 14 days. Serum renal biomarkers, oxidative stress markers, and histopathology were assessed. In HK-2 human renal tubular epithelial cells, cisplatin (20 µM) caused cytotoxicity, oxidative stress, mitochondrial depolarization, apoptosis, inflammatory cytokine release and ferroptosis. Pretreatment with ALIF (50–200 µg/mL) restored cell viability, reduced ROS and lipid peroxidation, preserved mitochondrial membrane potential and ATP, suppressed caspase-3 activation, downregulated Bax and ACSL4, attenuated NF-?B and cytokine release, and reactivated Nrf2 nuclear translocation with upregulation of HO-1, NQO1, and GPX4. In rats, ALIF significantly reduced elevated serum creatinine, BUN, uric acid, and electrolyte disturbances, while histopathology showed preserved renal tubular and glomerular architecture. These findings establish that ALIF provides dose-dependent nephroprotection against cisplatin toxicity through integrated modulation of oxidative stress, mitochondrial stability, apoptosis, inflammation, and ferroptosis. The Nrf2–HO-1–GPX4 axis appears central to this protective effect, validating the ethnomedicinal relevance of Ichnocarpus frutescens and supporting its potential as a nephroprotective adjunct in cisplatin chemotherapy.