AN02, a Naovel Curcumin Derivative, Orchestrates APC‐SMAD4‐Mediated CTLA‐4 Degradation for Ovarian Cancer Therapy

ABSTRACT Curcumin is a natural polyphenolic compound extracted from the rhizomes of Curcuma longa , exhibiting a wide range of biological activities, including anti‐inflammatory, 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)‐SMAD4 (SMAD family member 4)‐CTLA‐4 (Cytotoxic T‐Lymphocyte‐Associated Protein 4) molecular axis. Experimental results demonstrated that AN02 significantly inhibited ovarian cancer cell proliferation at very low concentrations, with its half‐maximal inhibitory concentration (IC 50 ) significantly lower than that of curcumin. Additionally, AN02 exerted its antitumor effects by activating the APC‐SMAD4 molecular axis and inhibiting the CTLA‐4 molecular axis. Silencing CTLA‐4 inhibits the proliferation and immune escape of ovarian cancer. Further molecular mechanism studies revealed that APC directly regulates the SMAD4‐CTLA‐4 molecular axis, while SMAD4 forms a chaperone relationship with CTLA‐4 and promotes CTLA‐4 degradation through the K48‐dependent 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‐SMAD4‐CTLA‐4 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‐term 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‐resistant ovarian cancer to provide new directions for precision treatment of ovarian cancer.