N-salicyloyl tryptamine derivatives as potential therapeutic agents for doxorubicin-induced hepatotoxicity via PI3K/AKT/HO-1 signaling pathway

Abstract

Doxorubicin (DOX) is a broad-spectrum antineoplastic agent with remarkable efficacy against various malignant tumors. However, its clinical application is severely limited by profound hepatotoxicity, wherein oxidative stress acts as a pivotal mechanism underlying DOX-induced hepatotoxicity. N -salicyloyl tryptamine derivatives (NSTs) have been reported to possess potent antioxidant activities. In the present study, NSTs were applied for the first time in DOX-induced hepatotoxicity with structural modifications to the scaffold. Through systematic screening, a novel compound A50 was identified as the most potent active candidate. Both in vitro (AML12 cell lines) and in vivo (mice model of DOX-induced hepatotoxicity) experiments demonstrated that A50 significantly enhanced superoxide dismutase (SOD) activity, reduced malondialdehyde (MDA) levels, stabilized mitochondrial membrane potential (MMP), and promoted adenosine triphosphate (ATP) production, thus effectively improving mitochondrial function and suppressing oxidative stress-mediated damage. Additionally, A50 decreased serum levels of liver injury biomarkers [alanine transaminase (ALT), aspartate transaminase (AST) and levels of proinflammatory cytokines [tumor necrosis factor-αα (TNF-α), interleukin-6 (IL-6)], inhibited lactate dehydrogenase (LDH) activity, and attenuated histopathological lesions in liver tissues, without affecting its anti-hepatocellular carcinoma activity. Mechanism investigations revealed the hepatoprotective effects of A50 were associated with activation of the PI3K/AKT/HO-1 signaling pathway, and these effects could be blocked by the PI3K-specific inhibitor LY294002 in vitro. In conclusion, A50 may alleviated DOX-induced hepatotoxicity by activating the PI3K/AKT/HO-1 pathway to inhibit oxidative stress-driven pathological processes, including mitochondrial dysfunction, inflammation, and apoptosis. These findings highlight A50 as a promising candidate for the treatment of DOX-induced hepatotoxicity.