2026-07-12 | The Angiopoietin-like Protein (ANGPTL) Axis in Dyslipidemia: Mechanisms, Cardiovascular Risk, and Emerging Therapies.

The angiopoietin-like protein (ANGPTL) 3-4-8 axis has emerged as a central regulator of lipoprotein lipase and lipid metabolism. This review examines the mechanistic basis of ANGPTL pathway modulation and therapeutic implications for cardiovascular risk reduction across diverse phenotypes of dyslipidemia. Genetic studies demonstrate that loss-of-function variants in ANGPTL3 and ANGPTL4 are associated with lower triglycerides and decreased coronary artery disease risk. Pharmacologic inhibition of ANGPTL3 with monoclonal antibodies and RNA-based therapies reduces triglycerides, remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) through mechanisms predominantly independent of the LDL receptor. Clinical trials with ANGPTL3 inhibitors have demonstrated marked LDL-C reductions in patients with homozygous familial hypercholesterolemia (HoFH), as well as broad lipid-lowering effects in patients with mixed dyslipidemia. Emerging strategies targeting the ANGPTL3/8 complex and ANGPTL4 further refine lipid-lowering effects, while early genome-editing data suggest the potential for durable ANGPTL3 suppression. Modulation of the ANGPTL-lipoprotein lipase axis is a novel strategy to address residual atherosclerotic risk beyond traditional LDL receptor-dependent therapies. ANGPTL3 inhibitors have been practice-changing in HoFH, and more broadly, ANGPTL-directed therapies hold promise for patients with mixed dyslipidemia to mitigate cardiovascular risk.

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2026-07-01 | Lipoprotein apheresis: From familial hypercholesterolemia and elevated lipoprotein(a) to emerging roles in peripheral arterial and renal disease.

Lipoprotein apheresis (LA) achieves acute reductions of 60-80% in LDL cholesterol and lipoprotein(a) [Lp(a)] through extracorporeal removal of apolipoprotein B-containing particles, and remains the cornerstone of treatment for homozygous familial hypercholesterolemia and severe heterozygous FH refractory to pharmacotherapy. Registry data, including more than 11 years of follow-up from the German Lipoprotein Apheresis Registry, document consistent reductions in major adverse cardiovascular events across all principal indications, though randomized controlled trial evidence is absent. The introduction of PCSK9 inhibitors and inclisiran has progressively reduced apheresis utilization for LDL-centric management, while potent RNA-based Lp(a)-lowering agents (pelacarsen, olpasiran, lepodisiran) in late-stage development may further reshape the field. Beyond traditional cardiovascular indications, accumulating observational evidence supports LA in peripheral arterial disease through pleiotropic rheologic and anti-inflammatory mechanisms, and in steroid-resistant focal segmental glomerulosclerosis through oxidized LDL clearance and podocyte rescue. This review synthesizes current evidence across cardiovascular, peripheral vascular, and renal indications, compares apheresis modalities, examines integration with emerging pharmacotherapies, and proposes a three-part trajectory for LA: progressive contraction in LDL-centric use, a persisting role in Lp(a)-driven disease until RNA-based agents demonstrate outcome benefit, and a mechanistically grounded but evidence-limited niche in selected pleiotropic vascular and renal phenotypes.

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2026-06-25 | A de novo LDLR mutation in severe familial hypercholesterolemia: case report, functional characterization, and a personalized gene correction strategy exploration.

Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by elevated plasma low-density lipoprotein resulting in cardiovascular disease (CVD). The harmful mutations of LDLR are the main cause of FH. Especially, there is no effective treatment options for homozygous FH (HoFH) patients. Numerous FH cases have been reported, but most mutations remain unvalidated and lack gene correction studies. The study aims to assess the pathogenicity of a novel mutation, LDLR c.331C>T (p.Gln111Ter), and seek its gene correction strategy. The study systematically evaluated a female HoFH patient and her family. Using CRISPR/Cas9 technology, a Huh7 cell line carrying the point mutation was constructed. The impact of this mutation on LDLR protein expression was confirmed by qPCR, Western blot (WB), and immunofluorescence. A high-fidelity gene correction system targeting the LDLR c.331C>T point mutation was established based on the prime editing (PE) technology. The HoFH patient exhibited a biallelic LDLR mutation comprising an LDLR c.1693_1696 del GGCA inherited from her mather and a de novo LDLR c.331C>T (p.Gln111Ter) mutation. In vitro validation indicated that the mutation impaired normal LDLR protein expression, and the candidate gene editing system achieved approximately 98% correction efficiency. LDLR c.331C>T is a likely pathogenic mutation, which canbe precisely corrected by PE technology. The study expands the spectrum of likely pathogenic mutations in FH and holds promise for personalized, precise gene therapy through customized therapeutic systems, potentially alleviating or curing HoFH-a current challenge in conventional clinical management.

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