Hepatic targeting in ASCVD: integrating lipid lowering and inflammation modulation from statins to gene editing

Atherosclerotic cardiovascular disease (ASCVD) continues to be a major global health burden, with substantial residual cardiovascular risk remaining. Growing evidence highlights the liver’s pivotal role in the onset and development of ASCVD through multiple interconnected pathways. As the metabolic center of the body, the liver regulates the synthesis, secretion, and clearance of several atherogenic lipoproteins while simultaneously serving as a systemic inflammation amplifier, producing cytokines, acute-phase proteins, and coagulation factors. Traditional liver-targeted therapies, such as statins, have demonstrated that regulating liver metabolism can confer significant cardiovascular benefits. Subsequently, advances in nucleic acid-based drugs and in vivo gene-editing tools have broadened this strategy, enabling accurate and durable modulation of hepatic gene expression. However, recent clinical trials suggest that improvements in laboratory biomarkers do not always translate into proportional reductions in major adverse cardiovascular events. Moreover, the long-term safety and durability of lipid nanoparticles and gene-editing platforms remain ongoing concerns. Future research should focus on the classification of patients based on multiple omics data, and distinguish those whose main problem is metabolic disorder from those who are mainly at high risk of inflammation, thereby facilitating personalized therapeutic targeting. Overall, current evidence indicates that the liver represents a convergent therapeutic target for modulating both lipid metabolism and inflammation, offering a promising opportunity for deeper and more durable cardiovascular risk reduction. The liver acts as a central regulator integrating lipoprotein metabolism and systemic inflammation in the pathogenesis of ASCVD. Traditional liver-targeted therapies, including statins and bempedoic acid, improve lipid profiles but do not fully eliminate residual cardiovascular risk. Nucleic acid therapeutics and in vivo gene editing enable precise modulation of hepatic gene expression and offer deeper intervention across lipid and inflammatory pathways. Reductions in biomarkers, including LDL-C, Lp(a) and hs-CRP, do not consistently translate into cardiovascular event reduction, emphasizing the need for outcome-driven evaluation of liver-targeted therapies. Safety concerns and patient heterogeneity highlight the need for individualized liver-targeted treatment in ASCVD.