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Beyond this classical pathway, PCSK9 exerts complex pleiotropic effects and interacts with various lipoproteins, contributing to cardiovascular and metabolic pathologies. This review synthesizes current knowledge on PCSK9 biology, its multi\u2010organ implications and evolving therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This narrative review summarizes current evidence from experimental, translational and clinical studies on PCSK9 biology and therapeutics. The literature examined includes studies on PCSK9 transcriptional regulation, post\u2010translational modifications, interactions with lipoproteins and the clinical development of established and emerging PCSK9\u2010targeting therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PCSK9 activity is modulated by several transcription factors (e.g., SREBP2, HNF1\u03b1) and post\u2010translational processes such as furin cleavage and sulfation. Clinically, elevated PCSK9 levels are linked to atherosclerosis progression, heart failure and adverse outcomes in infectious diseases and certain malignancies. Monoclonal antibodies (alirocumab, evolocumab) and siRNA (inclisiran) consistently reduce LDL\u2010C by 50%\u201360%. Emerging approaches include oral inhibitors which may broaden access to PCSK9\u2010targeting therapy, and CRISPR\u2010based gene\u2010editing strategies (e.g., VERVE\u2010102), which aim to achieve sustained LDL\u2010C lowering after a single treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>PCSK9 is a multifaceted protein with roles extending far beyond LDL\u2010C regulation. Understanding its diverse interactions is crucial for optimizing treatment in cardiovascular disease and potentially expanding its therapeutic application to metabolic and infectious conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/eci.70263","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T05:35:07Z","timestamp":1792388107000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proprotein Convertase Subtilisin\/Kexin Type 9: From Biology to Therapeutic Targeting in Cardiovascular Disease"],"prefix":"10.1111","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5213-4043","authenticated-orcid":false,"given":"Riccardo","family":"Rizzo","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences Universit\u00e0 Degli Studi di Milano  Milan Italy"},{"name":"IRCCS MultiMedica  Milan 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