{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T01:17:42Z","timestamp":1768439862490,"version":"3.49.0"},"reference-count":58,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Curcumin is a natural polyphenolic compound extracted from the rhizomes of\n                    <jats:italic>Curcuma longa<\/jats:italic>\n                    , exhibiting a wide range of biological activities, including anti\u2010inflammatory, antioxidant, antitumor, antibacterial, antiviral, and neuroprotective effects. However, its low oral absorption rate and poor bioavailability limit its clinical application. To address this issue, this study synthesized a novel curcumin derivative, AN02, which significantly improves the absorption rate and bioavailability while enhancing its antitumor activity. This study focused on the antitumor mechanism of AN02 in ovarian cancer, particularly its ability to inhibit ovarian cancer cell proliferation, invasion, and migration by regulating the APC (Adenomatous Polyposis Coli)\u2010SMAD4 (SMAD family member 4)\u2010CTLA\u20104 (Cytotoxic T\u2010Lymphocyte\u2010Associated Protein 4) molecular axis. Experimental results demonstrated that AN02 significantly inhibited ovarian cancer cell proliferation at very low concentrations, with its half\u2010maximal inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) significantly lower than that of curcumin. Additionally, AN02 exerted its antitumor effects by activating the APC\u2010SMAD4 molecular axis and inhibiting the CTLA\u20104 molecular axis. Silencing CTLA\u20104 inhibits the proliferation and immune escape of ovarian cancer. Further molecular mechanism studies revealed that APC directly regulates the SMAD4\u2010CTLA\u20104 molecular axis, while SMAD4 forms a chaperone relationship with CTLA\u20104 and promotes CTLA\u20104 degradation through the K48\u2010dependent ubiquitination pathway, thereby suppressing the malignant phenotype of ovarian cancer cells. These findings not only reveal the antitumor mechanism of AN02 but also provide new insights for the treatment of ovarian cancer. Animal experiments also demonstrated that AN02 significantly inhibits the proliferation of subcutaneous xenograft tumors in mice. As a novel curcumin derivative, AN02 exhibits significant antitumor activity and inhibits ovarian cancer progression by regulating the APC\u2010SMAD4\u2010CTLA\u20104 molecular axis. This study lays an important theoretical foundation for the development of novel antitumor drugs based on AN02, with significant clinical application potential. However, the long\u2010term toxicity and safety of AN02 require further investigation to establish safe dosage standards for clinical use. Future studies will focus on exploring combination therapy strategies of AN02 in cisplatin\u2010resistant ovarian cancer to provide new directions for precision treatment of ovarian cancer.\n                  <\/jats:p>","DOI":"10.1002\/mc.70048","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T19:15:29Z","timestamp":1761074129000},"page":"18-38","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AN02, a Naovel Curcumin Derivative, Orchestrates APC\u2010SMAD4\u2010Mediated CTLA\u20104 Degradation for Ovarian Cancer Therapy"],"prefix":"10.1002","volume":"65","author":[{"given":"Hairong","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology The First Affiliated Hospital of Ningbo University Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jingde County People's Hospital Xuancheng China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengna","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Oncology The Second Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pin","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology The First Affiliated Hospital of Ningbo University Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7153-9238","authenticated-orcid":false,"given":"Min\u2010Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology The Second Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2023.216332"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.7737"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.80590"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-022-01421-w"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-023-01281-2"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-024-02802-z"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psj.2024.104030"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.8220"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25052911"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252111492"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2013.11.021"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2015.2186"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/jf103873k"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp700113r"},{"issue":"3","key":"e_1_2_11_16_1","first-page":"515","article-title":"Chemistry of Curcumin: From Extraction to Therapeutic Agent","volume":"34","author":"Priyadarsini K. 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