Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased
profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.
Excerpts citing our work:
"In both human and animal studies, it has been revealed that the inherent lack of PCSK9 circulating in the bloodstream does not cause noticeable pathological conditions."
"Conversely, caffeine can raise the Ca2+ level in the ER of the liver to inhibit the expression of SREBP2 at the transcriptional level, thus decreasing the levels of PCSK9 as well as CVEs."
"Various preclinical and clinical studies have already identified a relationship between PCSK9 and NAFLD, suggesting that bloodstream PCSK9 is able to limit lipid uptake and their subsequent accumulation in the liver. Evidence showed that HFD could induce liver steatosis and raise both circulating and hepatic PCSK9 levels in mice."
"Various preclinical and clinical studies have already identified a relationship between PCSK9 and NAFLD, suggesting that bloodstream PCSK9 is able to limit lipid uptake and their subsequent accumulation in the liver. Evidence showed that HFD could induce liver steatosis and raise both circulating and hepatic PCSK9 levels in mice. Research by Demers and colleagues revealed PCSK9’s ability to regulate CD36 expression, a key influencer of FA uptake and a contributing factor to liver steatosis. Further studies also suggested that PCSK9 could control FA uptake in immortalized hepatocytes, dependent on CD36. Additionally, Pcsk9−/− mice showed an increase in liver lipid accumulation and CD36 expression, and when subjected to HFD, these mice developed severe liver steatosis and fibrosis. This ground-breaking research suggested that PCSK9 could degrade CD36 through interaction with its extracellular loop and mediation of its internalization. PCSK9 inhibition models observed an increase in hepatic TG both in cellular and animal models, indicating that a rise in hepatic levels of CD36 could increase NAFLD susceptibility."