Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

Background: Severe asthma is a chronic, difficult-to-treat disorder that significantly affects quality of life, and oral glucocorticosteroids are usually required. Many patients suffering from severe asthma exhibit T2 inflammation and may benefit from biological treatment. This study aims to evaluate changes in cytokine concentrations during therapy with benralizumab, dupilumab, and mepolizumab in severe eosinophilic asthma. Materials and Methods: In this prospective, single-center study, 39 patients with severe eosinophilic asthma received treatment with one of the above-mentioned biologics. Parameters, such as the cytokine profile (Human Th9/Th17/Th22 Luminex, Performance Assay 18-plex Fixed Panel, R&D Systems, Minneapolis, MN, USA) and additionally the Asthma Control Questionnaire (ACQ), mini-Asthma Quality of Life Questionnaire (mini-AQLQ), spirometry (FEV1, FEV/FVC), FeNO, and functional status, were assessed at baseline and after 3–4 months of therapy. Results: The biologic therapies demonstrated diverse effects on inflammatory biomarkers. Dupilumab showed the most pronounced decreases in CD40L, IL-6, and FeNO in comparison to other drugs. In turn, the greatest decrease in TNF-α concentration was observed in the group treated with mepolizumab. Conclusion: Changes in cytokine concentrations highlight the heterogenous immunomodulatory mechanisms of biologics and support personalized strategies based on inflammatory profiles. However, the results should be interpreted with prudence, as the concentrations of cytokines in blood serum fluctuate and the study sample size is small.