Lp(a) as a multisystem risk factor beyond the heart, and what RNA-based therapies could mean for renal, autoimmune and neurological disease, review argues (Life Sci 2025)

Lipoprotein(a) [Lp(a)] is a unique, genetically determined lipoprotein particle that has emerged as a significant independent risk factor for a wide spectrum of diseases beyond its well-established role in cardiovascular disease. Elevated Lp(a) levels are notoriously difficult to manage with conventional lipid-lowering therapies, posing a major clinical challenge. Recent advances have illuminated its complex pathophysiology, involving pro-inflammatory, pro-atherogenic, and pro-thrombotic pathways, which implicate Lp(a) in a diverse range of conditions including renal diseases, autoimmune disorders, and neurological conditions. Understanding the multifaceted role of Lp(a) across different organ systems is therefore of critical importance for developing targeted therapeutic strategies. A comprehensive synthesis of the evidence linking Lp(a) to these various pathologies is essential not only to consolidate our understanding of its mechanisms but also to identify patients at high risk across multiple disease domains. This review explores the molecular mechanisms by which Lp(a) contributes to disease pathogenesis, with a particular focus on inflammation and oxidative stress. We highlight the latest advances in novel, targeted therapeutic agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), which offer promising potential for specifically lowering Lp(a) levels. Furthermore, we discuss the implications of these therapies for modifying disease risk and improving clinical outcomes, offering hope for a paradigm shift in the management of Lp(a)-associated disorders.