Integrative single-cell sequencing and metabolomics reveal the immunometabolic regulatory network of alirocumab in atherosclerosis: Focus on the PCSK9-LOX-1-NF-κB-IL-6 axis and therapeutic prospects

Atherosclerosis (AS), the primary pathological basis for cardiovascular diseases, is characterized by a maladaptive interplay between lipid deposition and chronic inflammation. Although conventional lipid-lowering therapies such as statins effectively reduce low-density lipoprotein cholesterol (LDL-C), approximately 30 % of patients continue to experience recurrent cardiovascular events, underscoring the critical need for anti-inflammatory interventions. While the non-lipid-lowering effects of PCSK9 inhibitors like alirocumab are increasingly recognized, their specific immunometabolic mechanisms remain incompletely defined. This review integrates single-cell RNA sequencing (scRNA-seq) and metabolomics to systematically elucidate how alirocumab remodels the vascular inflammatory microenvironment via the PCSK9-LOX-1-NF-κB-IL-6 signaling axis. It highlights its regulation of macrophage polarization (M1/M2 balance) and discusses the therapeutic potential of targeting the PCSK9-lipoprotein(a)-inflammation triad, proposing a novel framework for precision medicine in AS. PCSK9 drives atherosclerotic pathology by activating the LOX-1/NF-κB inflammatory axis and stabilizing lipoprotein(a), alirocumab blocks this pathological cascade, and integrated single-cell RNA-seq and metabolomics decipher underlying immunometabolic mechanisms to support triple-pathway (PCSK9/Lp(a)/inflammation) targeted therapy for atherosclerosis.