Indole-3-acetic acid attenuates doxorubicin-induced liver injury by modulating oxidative stress, inflammation, and VEGF/FLT1 and Keap1/Nrf2/HO-1 signaling.

Abstract

Doxorubicin (DOX) remains an effective antineoplastic agent; however, its clinical use is frequently limited by adverse effects, including hepatotoxicity. Indole-3-acetic acid (IAA), a naturally occurring tryptophan-derived metabolite, has recently attracted attention because of its cytoprotective and immunomodulatory properties. The present study investigated the potential protective effect of IAA against DOX-induced liver injury and explored its effect on oxidative stress, inflammation, apoptosis, VEGF/FLT1 axis and Nrf2/HO-1 signaling. Rats received IAA (40 mg/kg) for 14 days and a single injection of DOX (15 mg/kg) on day 7. DOX induced marked hepatic injury, evidenced by elevated serum aminotransferases and ALP, reduced albumin, and histopathological abnormalities. These changes were accompanied by increased lipid peroxidation, upregulated Bax and caspase-3, and depletion of GSH, SOD and catalase. DOX also increased NF-κB, TNF-α, IL-1β, and Keap1 while suppressing IL-10, Nrf2, HO-1, and NQO-1. Furthermore, VEGF and FLT1 expression were significantly elevated following DOX exposure. Treatment with IAA attenuated liver damage, restored antioxidant status, reduced inflammatory cytokine production and NF-κB, and mitigated apoptosis through modulation of Bax, Bcl-2, and caspase-3. In addition, IAA ameliorated VEGF/FLT1 signaling, downregulated Keap1 and restored Nrf2, HO-1 and NQO-1 expression while simultaneously increasing HO-1 and NQO-1 enzymatic activities. Molecular docking analyses predicted favorable interactions between IAA and Keap1, HO-1, NF-κB p65, caspase-3, and FLT1. In conclusion, IAA treatment was associated with attenuation of acute DOX-induced hepatic injury, as evidenced by improvements in histopathological alterations, serum liver injury markers, oxidative stress parameters, inflammatory mediators, and apoptotic markers. The hepatoprotective activity of IAA appears to involve modulation of VEGF/FLT1 and Nrf2/HO-1 signaling. These findings identify IAA as a promising adjunctive candidate for reducing hepatic adverse effects associated with DOX therapy.