{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:59:31Z","timestamp":1790236771546,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    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                    <jats:italic>N<\/jats:italic>\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\n                    <jats:bold>A50<\/jats:bold>\n                    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\n                    <jats:bold>A50<\/jats:bold>\n                    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,\n                    <jats:bold>A50<\/jats:bold>\n                    decreased serum levels of liver injury biomarkers [alanine transaminase (ALT), aspartate transaminase (AST) and levels of proinflammatory cytokines [tumor necrosis factor-\u03b1\u03b1 (TNF-\u03b1), 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\n                    <jats:bold>A50<\/jats:bold>\n                    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,\n                    <jats:bold>A50<\/jats:bold>\n                    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\n                    <jats:bold>A50<\/jats:bold>\n                    as a promising candidate for the treatment of DOX-induced hepatotoxicity.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1929788","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:11:18Z","timestamp":1790233878000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["N-salicyloyl tryptamine derivatives as potential therapeutic agents for doxorubicin-induced hepatotoxicity via PI3K\/AKT\/HO-1 signaling pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuting","family":"Zhao","sequence":"first","affiliation":[{"name":"School of Basic Medicine, School of Pharmaceutical Science, Hengyang Medical School, University of South China","place":["Hengyang, Hunan, 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