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Despite optimal control of traditional lipid levels, elevated lipoprotein(a) [Lp(a)] remains a significant contributor to residual cardiovascular risk, affecting up to 20% of the global population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a literature search of PubMed\/Medline and Google Scholar until July 2025 to provide a comprehensive overview of the genetics, structure, metabolism, and molecular mechanisms underlying Lp(a)'s pathogenicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Structurally, Lp(a) consists of an LDL\u2010like core covalently bound to apolipoprotein(a) [apo(a)], a polymorphic glycoprotein characterized by kringle IV type 2 (KIV\u20102) repeat variability. This copy number variation is the primary determinant of apo(a) isoform size and plasma Lp(a) levels. Small isoforms are produced more efficiently, resulting in higher concentrations. Lp(a) is synthesized in hepatocytes, and its plasma levels are predominantly governed by production rather than clearance. It carries a high burden of oxidized phospholipids (OxPLs), which confer pro\u2010inflammatory and pro\u2010atherogenic properties. Lp(a) promotes arterial inflammation, endothelial dysfunction, monocyte activation and impaired fibrinolysis via competition with plasminogen. It also plays a direct pathogenic role in valvular calcification by delivering OxPLs and autotaxin to valve interstitial cells, triggering osteogenic signaling cascades.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>While environmental factors such as inflammation and hormonal status can transiently modulate levels, genetic variation overwhelmingly dictates lifelong Lp(a) burden. As novel agents targeting Lp(a) enter late\u2010stage clinical trials, mechanistic insights into Lp(a) biology will be essential to risk stratification and future clinical management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/eci.70133","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T12:23:46Z","timestamp":1759494226000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The biology of lipoprotein(a): From genetics to molecular mechanisms"],"prefix":"10.1111","volume":"56","author":[{"given":"Mark","family":"Atallah","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadim","family":"Nasrallah","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine Johns 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