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This underscores the urgent need to develop innovative drugs and treatment strategies to improve patient outcomes. This study examined the molecular pathways underlying troxerutin's therapeutic potential in HCC, providing information that could aid in the development of novel therapeutic strategies. Cell proliferation and apoptosis were assessed using CCK-8, EdU assays, and flow cytometry. Protein expression and mRNA alterations were analyzed by Western blotting and PCR, respectively. Cell migration and invasion were evaluated using Transwell assays, while tumor cell stemness was examined through sphere formation assays. Troxerutin's functional role was studied using in vivo models. Proteomic profiling of troxerutin-treated cells was performed using iTRAQ combined with LC\u2013MS\/MS to identify differentially expressed proteins (DEPs). Furthermore, luciferase reporter and ChIP assays were conducted to elucidate the underlying regulatory mechanisms. These findings demonstrate that troxerutin markedly inhibits HCC malignancy and stemness in both in vitro and in vivo models. Bioinformatics analysis indicated that the FOXO and SYK signaling pathways were predominantly enriched among the differentially expressed proteins. Mechanistically, we show that Syk dephosphorylation activates FOXO3 and facilitates its translocation into the nucleus. Moreover, we confirm that FOXO3 directly associates with the Syk promoter, thereby initiating its transcription. The present study reveals that troxerutin attenuates HCC progression by targeting the FOXO3\/Syk feedback loop, inhibiting the stem-like properties of HCC cells.<\/jats:p>","DOI":"10.1007\/s10565-026-10194-z","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T22:13:36Z","timestamp":1778192016000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Troxerutin suppresses the stemness of hepatocellular carcinoma via the Syk\/FOXO3 feedback loop"],"prefix":"10.1007","volume":"42","author":[{"given":"Shan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanhan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanrui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"10194_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3831\/KPI.2021.24.1.1","volume":"24","author":"Z Ahmadi","year":"2021","unstructured":"Ahmadi Z, Mohammadinejad R, Roomiani S, Afshar EG, Ashrafizadeh M. 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