Search Results (178)

Alzheimer’s disease (AD) is increasingly associated with alterations in cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme regulating low-density lipoprotein receptor (LDLR) degradation, has been implicated in AD through mechanisms involving amyloid-β (Aβ) processing, tau phosphorylation, and synaptic dysfunction. This review aimed to evaluate clinical, genetic, and experimental evidence regarding the role of PCSK9 in AD and its potential as a biomarker or therapeutic target. A systematic search was conducted in PubMed, Scopus, ScienceDirect, and Google Scholar (2020–2025) using predefined terms related to PCSK9 and Alzheimer’s disease. Eligible studies included clinical, in vivo, and in vitro investigations reporting PCSK9 expression, regulation, or inhibition in relation to AD pathology. Due to methodological heterogeneity, a narrative synthesis was performed. Forty-two studies met inclusion criteria. Preclinical findings consistently showed that elevated PCSK9 may indirectly promote Aβ accumulation, tau hyperphosphorylation, neuroinflammation, and cognitive decline, while genetic deletion or pharmacological inhibition of PCSK9 mitigates these effects. Clinical evidence was variable: several studies identified increased PCSK9 levels in cerebrospinal fluid or brain tissue of AD patients, often correlating with tau markers, but large-scale genetic and Mendelian randomization studies did not confirm a causal association. PCSK9 inhibitors, widely used in cardiovascular therapy, demonstrated potent LDL-C reduction without cognitive adverse effects. Experimental data suggest that PCSK9 contributes to AD-related pathology, whereas human evidence indicates a modulatory or biomarker role rather than a causative one. Despite strong preclinical data, human genetics lacks causal evidence for PCSK9 in Alzheimer’s. It may be a disease modifier or biomarker; its clinical relevance requires confirmation through longitudinal studies and CNS-penetrant therapies. Full article

Neural function relies on tightly regulated lipid metabolism to sustain membrane integrity, synaptic signaling, and energy production. Myelinating glia, particularly Schwann cells, require continuous lipid flux to build and maintain myelin, rendering them vulnerable to imbalances between lipid entry and oxidative capacity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), widely studied in hepatic cholesterol regulation, has emerging roles in the nervous system. In the central nervous system (CNS), local PCSK9 expression influences low-density lipoprotein receptor (LDLR) family abundance, neuronal survival pathways, and neuroinflammatory tone, although circulating PCSK9 has limited parenchymal access due to the blood–brain barrier (BBB). In the peripheral nervous system (PNS), recent evidence highlights a PCSK9–CD36 axis in Schwann cells; genetic Pcsk9 loss elevates CD36, increases fatty-acid influx, promotes lipid droplet expansion and acylcarnitine accumulation, and triggers mitochondrial stress that manifests as hypomyelination, C-fiber pathology, and selective small-fiber neuropathy. These findings suggest that PCSK9 normally restrains CD36-dependent transport to align lipid supply with metabolic demand. Clinically, PCSK9 inhibitors have demonstrated cardiovascular benefit without major neurocognitive signals, yet small-fiber outcomes have not been systematically assessed. This review integrates current evidence on PCSK9 biology across neural compartments, highlights mechanistic links to Schwann cell lipid handling, and outlines research priorities to resolve neural safety and therapeutic potential in lipid-driven neuropathies. Full article

Atherosclerosis as a multifactorial disease remains the first cause of death worldwide. Current oral lipid-lowering drugs (especially statins) reduce low-density lipoprotein cholesterol (LDLC) levels in the blood, but their clinical efficacy seems to be partially attributed to pleiotropic effects on different pathophysiologic factors of atherosclerosis extending beyond lipid-lowering properties such as anti-inflammatory, antithrombotic and antioxidative features. Novel drugs that interfere with proprotein convertase subtilisin/kexin type 9 (PCSK9) axis of LDL-C receptors (LDLRs) degradation, from the group of monoclonal antibodies (e.g., alirocumab, evolocumab) or small interfering RNA (siRNA), e.g., inclisiran, are effective in reducing LDLC as well. However, data depicting their antithrombotic and antiplatelet activity are scarce, whereas prothrombotic properties of PCSK9 are widely described. Thus, we performed a study to assess the effects of inclisiran on subclinical prothrombotic [fibrinogen, coagulation factor VIII (FVIII), plasminogen activator inhibitor-1 (PAI-1)] and platelet activation markers (platelet factor-4 (PF-4), soluble p-selectin (sCD62P)). Ten patients at high cardiovascular risk with concomitant heterozygous familial hypercholesterolemia (HeFH)—study group 1, and fourteen patients at very high cardiovascular risk without concomitant HeFH—study group 2, were recruited for the study. Lipid profile, subclinical prothrombotic and platelet activation markers were assessed at the beginning and after 3 months of therapy with inclisiran. During therapy, statistically significant reductions in both study groups were seen in total cholesterol levels (study group 1: from 287.6 ± 94.2 to 215.2 ± 89.1 (mg/dL), p = 0.022; study group 2: from 211.7 ± 52.7 to 147.6 ± 55.4 (mg/dL), p < 0.001) and LDL-c (study group 1: from 180.8 ± 73.3 to 114.7 ± 71.5 (mg/dL), p = 0.031; study group 2: from 129.6 ± 46.8 to 63.4 ± 43.6 (mg/dL), p < 0.001). Lipid profile changes were associated with significant decrease in the concentration of FVIII in both groups (study group 1: from 33.3 ± 22 to 22 ± 14.5 (ng/mL), p = 0.006; study group 2: from 37 ±16.9 to 29.3 ±16.4 (ng/mL), p = 0.002) and fibrinogen, but only in study group 2 (from 51.4 (33.2–72.7) to 42.6 (31.3–57.2) (µg/mL), p = 0.035). Among platelet activation markers, a significant decrease in PF-4 in study group 2 was noted (from 286 (272–295.5) to 272 (268–281.5) (ng/mL), p = 0.047). However, there were no statistically significant changes in PAI-1 and sCD62P throughout the study. In our study, inclisiran appeared to be an effective lipid-lowering drug in patients at high cardiovascular risk. Moreover, it was shown that beyond lipid-lowering properties, the drug may also partially affect thrombogenesis and platelet activation. Full article

Background/Objectives: Hypercholesterolemia remains a major risk factor for cardiovascular disease and a leading cause of global mortality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of low-density lipoprotein receptors (LDLR), thereby reducing LDL-cholesterol (LDL-C) clearance. While monoclonal antibodies (mAbs) targeting PCSK9 are effective, their short half-life requires frequent dosing and incurs high treatment costs. This study evaluates a novel peptide-based Anti-PCSK9 product aimed at providing sustained LDL-C reduction. Methods: A novel PCSK9 based-peptide conjugated to diphtheria toxoid (DT) was evaluated in various preclinical models: high-fat diet-fed C57BL/6 mice, APOB100/hCETP transgenic mice, BALB/c mice and normocholesterolemic non-human primates. Immunogenicity (Anti-PCSK9 antibody titers, binding affinity by SPR), pharmacodynamics (LDL-C levels, inhibition of PCSK9-LDLR interaction) and safety were assessed. Toxicity was evaluated in rodents, rabbits and dogs through clinical monitoring, histopathology, organ function and safety pharmacology studies. Results: The Anti-PCSK9 product induced robust and long-lasting immune response in all models antibody titers in BALB/c mice peaked by week 6 and persisted for 12 months. LDL-C reductions of 44% in APOB100/hCETP mice and 37% in C57BL/6 mice correlated with high antibody titers and strong PCSK9-binding affinities (85 and 49 RU), leading to 59% and 58% inhibition of PCSK9-LDLR interaction, respectively. Non-human primates showed sustained responses. No systemic toxicity was observed; injection-site reactions were mild and reversible. No adverse effects were detected on cardiovascular, neurological, or respiratory systems. Conclusions: This peptide-based Anti-PCSK9 therapy offers sustained efficacy and safety, representing a promising long-acting alternative for managing hypercholesterolemia. Full article

Dexamethasone, widely used as an exogenous glucocorticoid in clinical and animal practice, has recently been recognized as an environmental contaminant of concern. Existing evidence documents its ability to induce persistent dyslipidemia in adult offspring. In this study, plasma cholesterol levels in male rats exposed to dexamethasone prenatally (PDE) were increased. Meanwhile, developmental tracking revealed a reduction in hepatic low-density lipoprotein receptor (LDLR) promoter H3K27 acetylation (H3K27ac) and corresponding transcriptional activity across gestational-to-postnatal stages. Mechanistic investigations established glucocorticoid receptor/histone deacetylase2 (GR/HDAC2) axis-mediated epigenetic programming of LDLR through H3K27ac modulation in PDE offspring, potentiating susceptibility to hypercholesterolemia. Additionally, in peripheral blood mononuclear cells (PBMC) of PDE male adult offspring, LDLR H3K27ac level and expression were also decreased and positively correlated with those in the liver. Clinical studies further substantiated that male newborns prenatally treated with dexamethasone exhibited increased serum cholesterol levels and consistent reductions in LDLR H3K27ac levels and corresponding transcriptional activity in PBMC. This study establishes a complete evidence chain linking PDE with epigenetic programming and cholesterol metabolic dysfunction, proposing PBMC epigenetic biomarkers as a novel non-invasive monitoring tool for assessing the developmental toxicity of chemical exposures during pregnancy. This has significant implications for improving environmental health risk assessment systems. Full article

Background/Objectives: Hypercholesterolemia, accompanied by vascular inflammation, leads to the premature initiation and progression of atherosclerosis, and both are considered nowadays as well-established cardiovascular (CV) risk factors. For several years, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is), drugs that reduce the degradation of the receptors for low-density lipoprotein cholesterol (LDLRs), have appeared to be a very efficient lipid-lowering therapy among patients with complications resulting from atherosclerotic cardiovascular disease (ASCVD). Previous studies showed that drugs used to fight hypercholesterolemia (predominantly statins) have significant pleiotropic effects, including anti-inflammatory effects. To date, data on the potential impact of PCSK9 inhibitors, especially inclisiran, on the course of inflammation is still lacking. Therefore, we conceived a study to evaluate the effects of inclisiran on the markers of subclinical inflammation (e.g., pentraxin 3 (PTX3), interleukin-18 (IL-18), and soluble cluster of differentiation 40 ligand (CD40L)) and compared their magnitude in patients at high CV risk, with and without established heterozygous familial hypercholesterolemia (HeFH). Methods: A total of 24 patients at high cardiovascular risk, according to European Society of Cardiology (ESC) guidelines, with or without concomitant HeFH diagnosed using Dutch Lipid Clinic Network (DLCN) criteria, were enrolled in this study. Lipid concentrations and levels of subclinical inflammatory markers of atherosclerosis were measured at the beginning and after 3 months of therapy. Results: After three months of therapy with inclisiran, a statistically significant reduction included total cholesterol (TC): study group 1: from 287.6 ± 94.15 to 215.2 ± 89.08 [mg/dL], p = 0.022 and study group 2: from 211.71 ± 52.72 to 147.64 ± 55.44 [mg/dL], p < 0.001, and low-density lipoprotein cholesterol (LDL-c): study group 1: from 180.79 ± 73.33 to 114.65 ± 71.54 [mg/dL], p = 0.031 and study group 2: from 129.62 ± 46.75 to 63.39 ± 43.6 [mg/dL], p < 0.001. Moreover significant drops were observed in concentrations of PTX3: study group 1: from 1336.33 ± 395.15 to 1121.75 ± 351.17 [pg/mL], p = 0.013 and study group 2: from 1610.76 ± 537.78 to 1376.92 ± 529.19 [pg/mL], p = 0.017), and IL-18: study group 1: from 11.89 (9.72–13.98) to 9.15 (8.62–10.06) [pg/mL], p = 0.005 and study group 2: from 11.58 (10.87–16.97) to 9.65 (8.43–10.95) [pg/mL], p = 0.003). There were no significant changes in the levels of sCD40L. Conclusions: This study confirmed the ability of inclisiran to reduce LDL-c levels in patients at high cardiovascular risk just after one dose of the drug. Furthermore, it appeared that beyond its lipid-lowering effect, the drug may also affect some inflammatory processes involved in the initiation and progression of atherosclerosis. Full article

This study investigated whether exercise training improved cholesterol metabolism through modifying alternative splicing of the low-density lipoprotein receptor (LDLR). Blood lipids and expressions of LDLR splice variants were compared between exercise-trained and non-trained young adults with normal and high cholesterol. The expression of LDLR splice isoforms were examined using RT-PCR and the histone H3K36me3 by CHIP-assay in mouse liver following a 13-week normal or high-cholesterol-diet combined with or without 8 weeks of aerobic exercise-training. The influence of histone modifications on LDLR alternative splicing was examined in HepG2 cells (human liver cell-line). Expression levels of LDLR deletions in exons 4 and 12 (LDLR-∆Exon4 and LDLR-∆Exon12) were significantly higher in the obese adults with high-cholesterol. These LDLR splice variants were significantly lower in the exercise-trained than non-trained group with normal cholesterol. Thirteen weeks of high-cholesterol feeding increased LDLR-∆Exon14 expression in mice, which was diminished after 8 weeks of exercise training. When H3-K36me3 or the MORF-related gene on chromosomes 15 were overexpressed and interfered, the levels of LDLR-∆Exon4 and LDLR-∆Exon12 expression in HepG2 cells were significantly augmented and inhibited, respectively. Hypercholesterolemia was associated with augmented expressions of LDLR splice variants in obese adults and following high-cholesterol diet in mice. Aerobic exercise training prevented and reversed the dyslipidemia-related alternative splicing of LDLR pre-mRNA. The histone modifications contributed to the alternative splicing. Full article

Background/Objectives: Prostate cancer (PC) is among the most common malignancy in men. Several newly diagnosed patients have a locally advanced disease and distant metastasis at the initial diagnosis time. Castration-resistant PC (CRPC) patients have 100% recurrence incidence despite completing a therapeutic regimen, leading to high mortality. Androgen deprivation therapy and androgen inhibitors are initially effective, but resistance is inevitably developed. Epidemiological studies indicated that the Mediterranean diet, with high olive phenolic contents, is associated with a lower incidence of certain malignancies. This study aims at exploring the mCRPC progression and recurrence-suppressive and molecular effects of the major olive leaf phenolic glucoside (−)-oleuropein (OLE). Results: OLE downregulated the levels of proprotein convertase subtlisin/klexin type 9 (PCSK9) and normalized the low-density lipoprotein receptor (LDLR) in PC cells in vitro. Thus, a PCSK9-LDLR protein–protein interaction (PPI) in silico model was generated and used to assess OLE and its aglycone (OA) ability to bind at PCSK9 and thereby interfere with PCSK9-LDLR PPI. OLE perfectly filled the PCSK9 interface versus OA. Both OLE and OA showed virtual potential to interfere with PCSK9-LDLR PPI. OLE showed modest in vitro viability, migration, and clonogenicity suppressive effects on diverse human PC cell lines. OLE effectively suppressed mCRPC progression and recurrence in a nude mouse xenograft model. RNA-sequencing results proved the PCSK1, PCSK2, and PCSK9 downregulation in OLE-treated recurrent tumors versus vehicle control. Conclusions: Oleuropein is a novel lead useful for the control of mCRPC progression and the prevention of its recurrence via targeting PCSK9 expression and PPI with LDLR. Full article

Introduction and Objectives: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipid metabolism that is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and a high risk of atherosclerotic cardiovascular disease. Familial hypercholesterolemia is typically caused by mutations in the LDL receptor gene (LDLR), although other alterations may be found. The aim of this study was to perform a genetic study on a population identified through a new population-based diagnostic screen program for FH. Methods: Genetic variants in LDLR, apolipoprotein B (APOB), apolipoprotein E (APOE), proprotein convertase subtilisin/kexin type 9 (PCSK9), signal transducing Adaptor Family Member 1 (STAP1), low density lipoprotein receptor adaptor protein 1 (LDLRAP1) and lipase A, and lysosomal acid type lipase A (LIPA), as well as a genetic risk score, were evaluated in 84 individuals with a clinical diagnosis of FH based on the Dutch Lipid Clinics Network criteria (DLCN ≥ 6). These individuals were selected from a cohort of 752 patients with an abnormal lipid profile, obtained by screening existing centralized analytics. Results: A clinical diagnosis of FH was established in 17.9% of the patients evaluated, with mean LDL-C levels of 305.7 mg/dL (95% CI 250.4–360.9). Genetic variants were detected in 70.2% of these patients, with 50 different mutations identified, mainly in the LDLR. The most frequent pathogenic variants were c.1342C>T and c.313+1G>C. Null variants exhibited a more severe phenotype, and the risk score indicates that patients carrying genetic alterations have a 42% higher risk of developing cardiovascular disease. Conclusions: A high rate of genetic alterations was detected in patients with severe FH. In most cases, the phenotypic findings did not predict the genetic results, which provide important information regarding the cardiovascular risk of patients. Full article

Background: PCSK9 inhibitors (PCSK9i) represent a newer form of atherosclerosis treatment. Inflammation and haemostasis are key processes in the development of atherosclerosis. In this study, we investigated the influence of therapy with PCSK9i in patients with coronary artery disease (CAD) on regulators for lipoprotein homeostasis, inflammation and coagulation. Methods: Using quantitative polymerase chain reaction (qPCR), we measured the expression of the genes involved in lipoprotein homeostasis, namely for sterol regulatory element-binding protein 1 (SREBP1), SREBP2, low-density lipoprotein receptor (LDLR), hepatic lipase type C (LIPC), LDLR-related protein 8 (LRP8), and the genes associated with inflammation and coagulation, such as cluster of differentiation (CD) 36 (CD36), CD63, and CD14 in 96 patients with CAD and 25 healthy subjects. Results: Significant differences in the expression of the investigated genes between patients and healthy controls were found. Treatment with PCSK9i also resulted in significant changes in the expression of all studied genes. Conclusions: We established that PCSK9i may have a significant effect on the gene expression of lipid regulators, inflammatory markers, and coagulation parameters, independent of their lipolytic effect. Full article

Vesicular stomatitis virus (VSV) represents a significant advancement in therapeutic medicine, offering unique molecular and cellular characteristics that make it exceptionally suitable for medical applications. The bullet-shaped morphology, RNA genome organization, and cytoplasmic replication strategy provide fundamental advantages for both vaccine development and oncolytic applications. VSV’s interaction with host cells through the low-density lipoprotein receptor (LDL-R) and its sophisticated transcriptional regulation mechanisms enables precise control over therapeutic applications. The virus demonstrates remarkable versatility through its rapid replication cycle, robust immune response induction, and natural neurotropism. Recent technological innovations in VSV engineering have led to enhanced safety protocols and improved therapeutic modifications, particularly in cancer treatment. Attenuation strategies have successfully addressed safety concerns while maintaining the therapeutic efficacy of the virus. The molecular and cellular interactions of VSV, particularly its immune modulation capabilities and tumor-selective properties, have proven valuable in the development of targeted therapeutic strategies. This review explores these aspects, while highlighting the continuing evolution of VSV-based therapeutic approaches in precision medicine. Full article

Cardiovascular disease (CVD) and ischemic stroke (IS) are the primary causes of mortality worldwide. Hypercholesterolemia has been recognized as an independent risk factor for CVD and IS. Numerous clinical trials have unequivocally demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL-C) significantly mitigates the risk of both cardiac and cerebral vascular events, thereby enhancing patient prognosis. Consequently, LDL-C reduction remains a pivotal therapeutic strategy for CVD and IS. However, despite intensive statin therapy, a significant proportion of high-risk hypercholesterolemic patients fail to achieve sufficient reductions in LDL-C levels. In response to this challenge, an inhibitor targeting proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed as a therapeutic intervention for hyperlipidemia. Numerous randomized controlled trials (RCTs) have conclusively demonstrated that the combination of PCSK9 inhibitors and statins significantly enhances prognosis not only in patients with CVD, but also in those afflicted with symptomatic intracranial artery stenosis (sICAS). PCSK9 inhibitors significantly reduce LDL-C levels by binding to the PCSK9 molecule and preventing its interaction with LDLRs. This prevents degradation of the receptor and increases uptake of LDL-C, thereby decreasing its concentration in blood. Besides significantly reducing LDL-C levels, PCSK9 inhibitors also demonstrate anti-inflammatory and anti-atherosclerotic properties while promoting plaque stabilization and inhibiting platelet aggregation and thrombosis. This article aims to provide a comprehensive review based on the relevant literature regarding the evolving understanding of pleiotropic effects associated with PCSK9 inhibitors, particularly focusing on their impact on the cardiovascular system and central nervous system. Full article

Background/Objectives: This study investigated the potential of green algae-derived carotenoids as natural inhibitors of the proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism. PCSK9 promotes the degradation of low-density lipoprotein receptors (LDLR), thereby increasing blood cholesterol levels and elevating the risk of cardiovascular diseases. Methods/Results: We screened the pharmacophore fit score of 27 carotenoids with PCSK9 and identified 14 that were analyzed for binding affinity and molecular interactions. Astaxanthin, siphonaxanthin, and prasinoxanthin were identified as the top candidates, demonstrating strong binding affinity (−10.5, −10.3, and −9.4 Kcal/mol, respectively) and stable interactions with several known key residues within the active site of PCSK9, including Pro-331, Arg-357, Cys-358, Val-359, Asp-360, Ile-416, Leu-436, Thr-437, Pro-438, Leu-440, Arg-458, Val-460, Trp-461, Arg-476, Cys-477, Ala-478, Ala-649, Val-650, and Asp-651. Density functional theory analysis confirmed the stability of astaxanthin and its favorable electronic properties, suggesting its potential as an effective inhibitor. Molecular dynamics simulations of the PCSK9–astaxanthin complex revealed sustained structural stability and key interactions critical for maintaining the functional integrity of the protein. Conclusions: These findings provide evidence that specific carotenoids, particularly astaxanthin, may offer a cost-effective alternative to existing PCSK9 inhibitors, providing a potential approach for managing cholesterol levels and reducing cardiovascular risk. Pre-clinical and clinical validations are required to confirm the therapeutic potential of these compounds. Full article

Familial hypercholesterolemia is an autosomal hereditary disease defined by an increased level of low-density lipoprotein cholesterol (LDL-C), which predisposes significant risks for premature cardiovascular disorders. We present a family trio study: proband, a 13-year-old Kazakh girl with homozygous familial hypercholesterolemia (HoFH) and her parents. HoFH is much more rare and severe than a heterozygous form of the disorder. HoFH patients generally present with LDL-C levels exceeding 13 mmol/L, resulting in early and life-threatening cardiovascular events within the first decades of life. In cases of neglected treatment, young patients have a risk of death from coronary diseases before the age of 30. The aim of this research was to identify genetic mutations in the affected patient and her parents. Genetic testing was necessary due to highly elevated LDL-C levels and the presence of multiple xanthomas. Targeted next-generation sequencing (NGS) was performed in this study using the Illumina TruSight cardio panel, which targets 174 genes related to cardiac disorders. The girl was diagnosed with HoFH based on the results of genetic testing. A biallelic mutation was observed in exon 3 of the low-density lipoprotein receptor (LDLR): c. 295 G>A (p.Glu99Lys). Sanger sequencing confirmed that the mutant gene was inherited from both parents. After confirming the genetic diagnosis of HoFH, the patient was treated with LDL apheresis and statins. This case report is the first study of HoFH in a pediatric patient from the Central Asian region. Globally, it emphasizes the need for increased clinical awareness among healthcare providers, as early detection and intervention are important for improving outcomes, particularly in pediatric patients with this rare genetic disorder. Full article

Background: Several Previous studies indicate that consuming krill oil may aid in reducing hypercholesterolemia and improving cholesterol metabolism. Therefore, our study was designed to investigate the effectiveness of Antarctic krill oil (Euphausia superba) (ESKO) in combating obesity and lowering fat/lipid/cholesterol levels. Methods: The study aimed to investigate the molecular docking model targeting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) using ESKO-derived eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and astaxanthin. In this study, histological alterations in the liver of the obesity model (ICR male mouse), obesity-related or antioxidant markers in both liver and serum, the molecular mechanisms in HepG2 cells and liver tissue, and HMGCR activity were analyzed. Results: Our findings revealed that a high-fat diet (HFD) significantly led to increased oxidative stress, obesity-related indicators, and cardiovascular-associated risk indices. However, ESKO effectively mitigated HFD-induced oxidative stress, fat accumulation, and the suppression of low-density lipoprotein receptor (LDLR) or activation of related molecular pathways. This was achieved through improvements in metabolic parameters, including CD36/liver X receptor α (LXRα)/sterol regulatory element-binding protein 1c (SREBP1c), proprotein convertase subtilsin/kexin type 9 (PCSK-9), and HMGCR, ultimately ameliorating HFD-induced hypercholesterolemia and obesity. Conclusions: These beneficial findings indicate that ESKO might have significant potential for preventing and treating obesity-related disorders. Full article