👉PCSK9 targeting: from extracellular inhibition to genome editing 👆An important biological distinction as PCSK9 therapies evolve: 1⃣ Monoclonal antibodies neutralize circulating extracellular PCSK9, preventing PCSK9-mediated LDLR degradation. 2⃣ Inclisiran uses hepatocyte-targeted siRNA to reduce hepatic PCSK9 synthesis, thereby decreasing both intracellular production and circulating PCSK9. 3⃣ Gene-editing approaches aim to produce a durable reduction in hepatic PCSK9 expression through a one-time genomic intervention. 🤔 Why does this distinction matter? 👆PCSK9 biology may extend beyond LDLR regulation. Preclinical evidence implicates intracellular PCSK9 in apoB-100 stability/VLDL secretion, CD36 regulation, fatty-acid uptake, and hepatic lipid partitioning. 👆Human PCSK9 loss-of-function genetics and current pharmacological experience are reassuring. However, long-term pharmacological inhibition and permanent genomic modification are not biologically identical interventions. 👉 LDL-C lowering is the expected consequence. The key question for the gene-editing era is whether durable alteration of hepatic PCSK9 expression has metabolic consequences beyond LDL-C that become relevant over decades. 👉As we move toward one-time therapies, understanding the non-canonical biology of PCSK9 becomes increasingly important. @society_eas 🔓🔗doi.org/10.1016/j.jlr.2026.1…