Pcsk9 Promotes Progression Of Anaplastic Thyroid Cancer Through Ecadherin Endocytosis Yu Zhang Wei Su Xiaoyu Ji Zhou Yang Qing Guan Yuanxin Pang Linkun Zhong Yu Wang Jun Xiang by Yu Zhang & Wei Su & Xiaoyu Ji & Zhou Yang & Qing Guan & Yuanxin Pang & Linkun Zhong & Yu Wang & Jun Xiang 101038/S41419025076901 instant download after payment.

Although anaplastic thyroid cancer (ATC) constitutes only 1–2% of all thyroid malignancies, it is associated with an exceptionallyhigh mortality rate, accounting for 14–39% of thyroid cancer-related deaths. In this study, we identified the critical role ofProprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in ATC progression. Proteomic analysis revealed E-cadherin as a key mediatorof PCSK9-driven malignancy in ATC. Mechanistically, PCSK9 promotes the degradation of E-cadherin through the lysosomalpathway. Furthermore, the loss of the p53 function, particularly the R248Q mutation, de-repressed PCSK9 expression at thetranscriptional level. Notably, the PCSK9 inhibitor PF-846 considerably suppressed ATC proliferation and metastasis in both in vitroand in vivo models. In conclusion, PCSK9 enhances ATC malignancy by regulating E-cadherin degradation via the lysosomal1234567890();,:pathway, underscoring its potential as a promising therapeutic target.Cell Death and Disease (2025) 16:362 ;