Role of PCSK9 in hallmarks of cancer: From mechanisms to interventions (Review).

Although the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in regulating cholesterol homeostasis through low-density lipoprotein receptor (LDLR) is well established, accumulating evidence underscores its broader involvement in diverse biological processes such as angiogenesis and immunoregulation. These functions implicate PCSK9 in the pathogenesis of various human diseases, including cancer. Recent studies have revealed that PCSK9 mediates the lysosomal degradation of multiple substrates beyond LDLR, thereby expanding its potential importance in oncology. To the best of our knowledge, the present review summarized for the first time the identified repertoire of PCSK9 substrates, emphasising how these interactions enable PCSK9 to regulate novel biological pathways independently of cholesterol metabolism. Next, PCSK9 genetic variants were compiled, documented and discussed, focusing on how they influence disease susceptibility and progression by modulating PCSK9 activity or expression. Finally, the present review elaborated on the mechanisms by which PCSK9 contributes to several hallmarks of cancer, including sustained proliferative signaling, invasion and metastasis, metabolic reprogramming, angiogenesis and tumor immune evasion through the modulation of specific substrates. These insights highlight its relevance as a therapeutic target. The current review also provides an overview of ongoing clinical trials evaluating PCSK9 inhibitors, either as monotherapy or in combination with other anticancer strategies. Altogether, these advances lay a foundation for personalized and precision cancer therapy.