Background: Atherosclerosis (AS) is a chronic inflammatory vascular disease in which ferroptosis plays a crucial role. While the combination of polydatin (PD) and Hawthorn leaf flavonoids (HLF), termed PD and HLF combination (PH), is effective against AS, its impact on plaque vulnerability and the underlying mechanisms remain unclear. Methods: ApoE^−/− mice were fed a high-fat diet (HFD) for 12 weeks to establish an AS model and treated with PD, HLF and Simvastatin for 8 weeks. Histological characterization of atherosclerotic lesions was performed using pathological staining. Transmission electron microscopy (TEM) was used to evaluate mitochondrial damage. Lipid peroxidation levels were assessed using ELISA. Immunofluorescence staining was performed to verify Nrf2 nuclear translocation. Expression of the Nrf2/HO-1/GPX4 axis was detected using Western blotting and PCR. Results: HFD significantly promoted AS lesion formation and instability, and caused severe iron overload and lipid peroxidation in atherosclerotic lesions. PH significantly reduced dyslipidemia and suppressed atherosclerotic plaque progression in ApoE-/- mice. Meanwhile, the PH combination visibly reduced iron accumulation and improved mitochondrial ultrastructure. Additionally, PH combination decreased the levels of ROS, MDA, 4HNE, 8-OHdG, and Fe²⁺, while increasing GSH levels. Further studies showed that the PH combination enhanced the translocation of Nrf2 into the nucleus, HO-1, GPX4, SLC7A11, FPN1, and FTH1 expression, and inhibited cytoplasmic Nrf2 and TFR1 expression. Conclusion: PH combination reduced the instability of atherosclerotic lesions in ApoE^−/− mice by modulating iron metabolism and lipid peroxidation through activation of the Nrf2/ HO-1/GPX4 axis.

Although low-density lipoprotein cholesterol (LDL-C) can now be effectively reduced, substantial residual risk of acute ischemic cardiovascular events persists. Lipoprotein(a) [Lp(a)] is an established causal risk factor for atherosclerotic cardiovascular disease (ASCVD), yet its mechanistic links to plaque vulnerability and their clinical implications remain incompletely understood. Clinical imaging studies have associated elevated Lp(a) with plaque progression and features of vulnerability, including lipid-rich necrotic cores, macrophage accumulation, and thin fibrous caps, suggesting that Lp(a)-associated risk may involve destabilization during plaque progression. This review draws on imaging and pathological evidence to examine the potential mechanisms underlying these associations and their implications for clinical risk stratification and preventive decision-making. The apolipoprotein(a) [apo(a)] component unique to Lp(a), together with the oxidized phospholipids (OxPL) it carries, may contribute to plaque vulnerability by sustaining vascular inflammation, promoting necrotic core expansion, and influencing fibrous cap stability and intraplaque neovascularization. Integrating circulating Lp(a) levels with plaque imaging features and baseline cardiovascular risk may help identify individuals at high risk in primary prevention and evaluate residual risk in secondary prevention, informing earlier or more intensive efforts to manage modifiable risk factors. Alongside established preventive measures, therapies aimed at lowering Lp(a) may provide an additional approach to reducing residual risk. In trials conducted to date, substantial reductions in Lp(a) have been observed with antisense oligonucleotides, small interfering RNAs, and oral small-molecule inhibitors; some agents have demonstrated sustained effects and favorable safety profiles. However, whether therapies targeting Lp(a) reduce cardiovascular event risk remains to be established through robust evidence from large cardiovascular outcome trials.

Atherosclerosis (AS) is a chronic inflammatory disorder of the medium and large arteries, characterized by lipid accumulation within the arterial wall and a sustained inflammatory milieu, and it remains a leading cause of cardiovascular morbidity and mortality worldwide. Glycolysis and neutrophil extracellular traps (NETs) are both involved in the initiation and progression of AS in part through effects on endothelial function, platelet activation, lipid metabolism, and the inflammatory microenvironment. This article reviews the roles of NETs and glycolysis in AS, elucidates the mechanisms underlying NETosis, and discusses the association between glycolysis and NETosis. Finally, the article discusses the potential value of glycolytic inhibitors in the treatment of AS, with the aim of providing new perspectives for the diagnosis and treatment of AS and related cardiovascular diseases.

Background: Polydatin has shown anti-inflammatory, antioxidant, and cytoprotective effects in preclinical studies. Its development is limited by low oral bioavailability, extensive metabolism, and poorly defined tissue exposure. Objectives: This review summarizes the pharmacology and delivery systems of polydatin, distinguishes nano from non-nano formulations, and examines the evidence for improved exposure, tissue delivery, safety, and clinical translation. Methods: Relevant studies were identified through a structured PubMed search and assessed by formulation type, administration route, comparator, and reported endpoints. Results: Delivery strategies include liposomes, polymeric and polysaccharide nanoparticles, lipid-based formulations, inclusion complexes, solid-state systems, hydrogels, local matrices, and targeted systems. Only a few oral formulations have been compared directly with free polydatin using quantitative pharmacokinetic measurements. Many injectable and local studies report release, cellular uptake, fluorescence distribution, or pharmacodynamic effects, but these findings do not by themselves demonstrate improved bioavailability or drug-specific targeting. Evidence on repeat-dose toxicity, immunogenicity, carrier clearance, and manufacturing consistency remains limited. No clinical study of a polydatin nanocarrier was identified. Conclusions: Further development requires appropriate free-polydatin controls, measurement of polydatin and its metabolites, exposure–response analysis, fuller safety assessment, and reproducible product characterization.

Atherosclerosis (AS), the pathological basis of cardiovascular diseases, remains a leading global cause of mortality. Its pathogenesis involves chronic inflammation, impaired clearance of apoptotic cells (efferocytosis), and lipid dysregulation within the arterial wall. The CD47-SIRPα signaling axis, a key immune checkpoint, has been identified as a critical regulator integrating these processes in the atherosclerotic plaque microenvironment. This review systematically details the multifaceted role of the aberrantly activated CD47-SIRPα axis in driving AS progression. We elaborate on its molecular architecture and how it pathologically inhibits macrophage efferocytosis by disrupting cytoskeletal dynamics and integrin-mediated adhesion. The axis concurrently sustains a pro-inflammatory state within plaques and disrupts cholesterol homeostasis by promoting lipid influx and inhibiting efflux, thereby accelerating foam cell formation. We further evaluate emerging therapeutic strategies targeting this axis, including monoclonal antibodies, engineered SIRPα-Fc fusion proteins, and multifunctional nanocarriers designed for plaque-targeted delivery. These approaches aim to restore efferocytosis, mitigate inflammation, and resolve lipid accumulation. While preclinical results are encouraging, challenges such as cell-type-specific effects, potential on-target hematological toxicity, and the need for precise delivery persist. Therapeutic modulation of the CD47-SIRPα axis presents a promising immunometabolic strategy for AS. Future directions should focus on developing cell- or context-selective modulators to enhance safety, identifying biomarkers for patient stratification, and rationally combining these novel agents with established lipid-lowering and anti-inflammatory therapies to address the residual risk in atherosclerotic cardiovascular disease.