Guidelines
SREBP1, gut-derived TMAO, and Lp(a) all feed 'residual risk' left after LDL-C control, precision-medicine review argues for guideline-integrated management (J Vis Exp 2025)
Original title: Precision Management of Dyslipidemia in Atherosclerosis: Mechanisms, Therapeutic Strategies, and Future Directions
This review frames dyslipidaemia's molecular network as the target for precision atherosclerosis prevention, highlighting sterol regulatory element-binding protein 1 (SREBP1) and Lp(a) as pivotal regulators of lipid synthesis and transport, alongside gut microbiota-derived metabolites such as trimethylamine N-oxide and short-chain fatty acids that activate inflammatory pathways and promote lipid deposition through inter-organ signalling. It notes that many patients with LDL-C at goal still have cardiovascular events, a 'residual risk' driven primarily by elevated non-HDL-C, abnormal Lp(a), and an imbalanced triglyceride-to-HDL-C ratio, exposing the limits of LDL-C-only management. The review surveys emerging targeted therapies, including PCSK9 inhibitors, siRNA-based treatments, and the Lp(a)-lowering agent pelacarsen, and calls for integrating the 2023 Chinese Guidelines for Lipid Management with imaging and AI-assisted decision-making to deliver personalised drug selection, efficacy monitoring and long-term follow-up.
Original abstract
Dyslipidemia is a central driver in the initiation and progression of atherosclerosis (AS). The chronic inflammation and endothelial injury triggered by dyslipidemia are key pathological events in AS development. Elucidating the molecular network underlying dyslipidemia and developing precise interventions are critical for achieving precision prevention and treatment of AS. Recent studies have demonstrated that sterol regulatory element-binding protein 1 (SREBP1) and lipoprotein(a) [Lp(a)] play pivotal roles in the regulation of lipid synthesis and transport. Additionally, gut microbiota-derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), can activate inflammatory pathways and promote lipid deposition via inter-organ signaling axes, thereby accelerating the progression of AS. However, clinical studies have revealed that even when low-density lipoprotein cholesterol (LDL-C) levels are within the recommended range, a significant number of patients continue to experience cardiovascular events. This indicates the widespread presence of "residual risk". Such residual risk is primarily driven by elevated non-high-density lipoprotein cholesterol (non-HDL-C), abnormal levels of Lp(a), and imbalances in the triglyceride to HDL-C (TG/HDL-C) ratio, highlighting the limitations of traditional therapies in comprehensive lipid profile management. Emerging targeted therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, small interfering RNA (siRNA)-based treatments, and Lp(a)-lowering agents like pelacarsen, represent promising strategies for more precise lipid modulation. With the continuous advancement of related research, the precise management of AS will increasingly rely on deeper mechanistic insights and individualized therapeutic strategies. Current strategies for AS prevention and treatment focus on understanding key pathways, including lipid metabolism, inflammation, and vascular dysfunction, to develop targeted therapies. The integration of the 2023 Chinese Guidelines for Lipid Management, imaging, and AI-assisted decision-making will promote data-driven, precision medicine. Personalized drug selection, efficacy monitoring, and long-term follow-up will optimize clinical outcomes and enhance prevention strategies for high-risk patients.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.