Protective Effect of Lycopene Against Oxaliplatin-Induced Nephrotoxicity by Modulation NF-κB/TNF-α/IL-1β, P53/Bax/Bcl2, and PI3K/AKT/mTOR Signaling Pathway

Oxaliplatin (OXI), a platinum-based chemotherapeutic agent commonly used in colorectal Cancer treatment, has been linked to significant nephrotoxicity involving apoptosis, endoplasmic reticulum (ER) stress, inflammation, oxidative stress, and autophagy. This study investigated the potential mechanisms involved in kidney damage caused by OXI and explored the renoprotective effects of lycopene (LP) in renal tissues of rats. Biochemical analyses revealed that OXI administration led to elevated serum urea and creatinine levels, increased lipid peroxidation (MDA), and decreased antioxidant defense (SOD, CAT, GPx, GSH), accompanied by suppression of the Nrf-2/HO-1 pathway. Inflammatory markers such as NF-κB, IL-1β, COX-2, TNF-α, and iNOS were significantly upregulated, along with ER stress-related genes (GRP78, ATF6), apoptotic markers (p53, Bax, Bcl-2), and key mediators of autophagy (Beclin-1, JNK). Additionally, Western blot and immunohistochemistry results indicated increased expression of AKT, mTOR, and PI3K proteins in the OXI group, suggesting altered survival signaling. LP treatment ameliorated these pathological alterations by restoring antioxidant enzyme activities, downregulating proinflammatory and proapoptotic signals, mitigating ER stress and autophagy activation, and reducing PI3K/AKT/mTOR protein expression. These findings demonstrate that LP exerts a renoprotective effect against OXI-induced kidney injury through multi-targeted molecular mechanisms, including modulation of inflammation, oxidative stress, autophagy, apoptosis, and survival signaling pathways.