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AKR1B15, a lesser-studied member of the aldo-keto reductase family, shares high sequence similarity with AKR1B10, but its role in HCC remains unclear. Therefore, this study aimed to investigate the biological function of AKR1B15 in HCC and its involvement in oncogenic signaling pathways. Bioinformatic analysis of gene expression datasets and patient tissue samples was used to evaluate AKR1B15 expression and prognostic relevance. Functional assays were conducted following AKR1B15 knockdown, including CCK-8, colony formation, transwell, wound healing, flow cytometry, and xenograft models. Western blotting and immunofluorescence were employed to assess phosphorylation of key signaling molecules. AKR1B15 expression was significantly elevated in HCC tissues and associated with higher pathologic T stage and worse disease-specific survival (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05). AKR1B15 knockdown inhibited HCC cell proliferation, invasion, and migration (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01), and promoted apoptosis (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). In vivo, AKR1B15 depletion suppressed tumor growth and reduced Ki-67 expression. Mechanistically, silencing AKR1B15 decreased phosphorylation of p53 (Ser15), PI3K (Tyr458\/199), AKT (Ser473), mTOR (Ser2448), and E2F1 (S364), indicating inhibition of the p53-PI3K-AKT-mTOR-E2F1 axis. AKR1B15 promotes HCC progression and is associated with activation of the p53-PI3K-AKT-mTOR-E2F1 signaling pathway. It may serve as a novel diagnostic marker and therapeutic target in hepatocellular carcinoma.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-61264-5","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T02:05:12Z","timestamp":1784685912000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AKR1B15 promotes hepatocarcinogenesis by activating the p53-PI3K-AKT-mTOR-E2F1 signaling pathway"],"prefix":"10.1038","volume":"16","author":[{"given":"Jie","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinting","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixin","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenwei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"3","key":"61264_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray, F. et al. 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