Identification of XD23 as a potent inhibitor of osteosarcoma via downregulation of DKK1 and activation of the WNT/β-Catenin pathway

Osteosarcoma, the most prevalent malignant bone tumor, is notorious for its aggressive growth and invasiveness. The highly mutable genome of osteosarcoma has made identifying a key oncogene challenging, hindering the development of targeted treatments. Our study validates the effectiveness of XD23, an anti-cancer agent we previously identified, in curbing osteosarcoma proliferation, metastasis, EMT differentiation, and bone destruction and promoting osteosarcoma apoptosis. It further elucidated that XD23 thwarts osteosarcoma by suppressing DKK1 expression, which in turn activates the WNT-β/Catenin pathway. This research presents the concrete evidence of DKK1's involvement in osteosarcoma development, offering a foundation for the development of DKK1 inhibitors as novel treatments for this disease.

骨肉瘤（Osteosarcoma）是临床最常见的恶性骨肿瘤，以侵袭性生长与高侵袭性为显著特征。骨肉瘤基因组的高度突变特性使得关键致癌基因的鉴定极具挑战性，进而阻碍了靶向治疗的研发进程。本研究验证了我们此前鉴定得到的抗癌制剂XD23的抗肿瘤效果，其可有效抑制骨肉瘤的增殖、转移、上皮间质转化（EMT）分化与骨破坏，并促进骨肉瘤细胞凋亡。本研究进一步阐明，XD23通过抑制DKK1（Dickkopf相关蛋白1）的表达阻滞骨肉瘤进展，而DKK1表达被抑制后可激活WNT-β/β-连环蛋白信号通路。本研究为DKK1参与骨肉瘤的发生发展提供了确凿证据，同时为以DKK1抑制剂为核心的新型骨肉瘤治疗方案的研发奠定了理论基础。