Alantolactone protects against doxorubicin-induced nephrotoxicity by modulating Nrf2/HO-1, NF-κB, and Bax/Bcl-2...

BACKGROUND: Doxorubicin (DOX) is a widely prescribed chemotherapeutic agent, but its therapeutic use is frequently restricted due to its harmful effects on the kidneys. This research evaluated the nephroprotective properties of alantolactone (ATL), a naturally sourced sesquiterpene lactone, in a rat model of DOX-induced kidney injury, along with computational analysis of its molecular binding interactions. METHODS AND RESULTS: Male Wistar rats were randomly assigned to five groups: Control, ATL (10), DOX, ATL (5) + DOX, and ATL (10) + DOX. The Control and DOX groups received 0.5% sodium carboxymethyl cellulose orally for 18 days, whereas ATL was given orally at 10 mg/kg in the ATL-alone group. ATL was also administered orally at 5 or 10 mg/kg in the respective co-treatment groups. On day 17, DOX (20 mg/kg, i.p.) was administered to the DOX and co-treated animals. Renal function was assessed through serum biomarkers; oxidative stress (MDA, SOD, CAT), inflammatory markers (IL-6, TNF-α, NF-κB p65), and apoptosis-related genes (Bax, Bcl-2) were evaluated using biochemical methods, immunohistochemistry and qRT-PCR. Expression of Nrf2 and HO-1 was analysed, and molecular docking assessed interactions of ATL and DOX with Keap1 and TNF-α. ATL co-administration significantly alleviated DOX-induced renal impairment by reducing oxidative stress, inflammation, and apoptotic responses, while enhancing Nrf2 and HO-1 expression. Docking studies demonstrated strong binding affinity of ATL to Keap1 and TNF-α. CONCLUSION: ATL confers nephroprotection against DOX-induced toxicity, potentially through its antioxidant, anti-inflammatory, and anti-apoptotic effects linked to Nrf2 and HO-1 activation.