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Paneth cell metaplasia (PCM), a metaplastic change associated with chronic inflammation in ulcerative colitis (UC), may be linked to UC-associated neoplasia (UCAN). However, no endoscopic method currently exists for detecting PCM. This study aimed to develop and validate a novel endoscopic staining technique-CV-SCAN-for identifying PCM and UCAN, and to explore the molecular characteristics of the stained areas. This retrospective observational study included 131 patients with UC undergoing surveillance colonoscopy. CV-SCAN involved spraying an ultra-diluted solution (0.006%) of crystal violet from the descending colon to the rectum. Biopsies were obtained from stained and non-stained areas and evaluated histologically and molecularly. RNA expression profiles were analyzed via microarray and real-time RT-PCR. The diagnostic performance of CV-SCAN for detecting PCM was assessed, along with its correlation with UCAN history. CV-SCAN visualized sharply demarcated, purple-stained areas corresponding to PCM or UCAN. PCM was significantly associated with a history of UCAN. Uniform, dark staining was characteristic of PCM, while UCAN showed heterogeneous staining with small round pits. CV-SCAN achieved a sensitivity of 81.3% and a specificity of 84.9% for PCM detection. Molecular analysis revealed upregulation of Paneth cell-specific (DEFA5, DEFA6), small intestinal (CCL25, APOC3), and UCAN-associated (IL17RC) genes, along with downregulation of SATB2 in stained areas. CV-SCAN is a novel and effective endoscopic staining method for detecting PCM and UCAN in patients with UC. It enables risk stratification through direct visualization of precancerous changes and may facilitate early detection and targeted surveillance. Show less

Persistent chylomicronemia is associated with severe hypertriglyceridemia (sHTG) and plasma triglycerides (TG) levels sustainably > 10 mmol/L (880 mg/dL) despite lipid lowering therapies. The main risk of persistent chylomicronemia is acute pancreatitis (AP). During the second and third trimester of pregnancy, TG levels significantly increase, which represents a serious risk of AP in women with preexisting chylomicronemia. New emerging therapies such as plozasiran, a GalNAc-conjugated small interfering RNA (siRNA) against ApoC3, are developed to manage persistent chylomicronemia, but no data are currently available on their safety and efficacy during pregnancy. We report herein the case of a woman with persistent chylomicronemia randomized in the PALISADE study to receive plozasiran 25 mg quarterly, who had an unplanned pregnancy during the clinical trial. The 34-year-old patient received one dose of plozasiran 8 weeks before conception and the experimental treatment was ceased afterwards. The pregnancy went well, TG levels did not rise above 10 mmol/L (880 mg/dL) during the whole pregnancy, even during the last two trimesters where TG levels usually increase two- to four-fold from baseline and she did not experience any AP episode. She delivered a healthy baby at 39 weeks. This case suggests that plozasiran might be safe for the mother and the fetus and could prevent incremental pregnancy-driven TG elevation and occurrence of AP in women with sHTG. This is consistent with the long duration of action and hepatic half-life of plozasiran in clinical studies where TG levels remained sustainably lower than baseline > 9 months after the last injection. Show less

Genetic determinants play a central role in the development of dyslipidemias, which are major contributors to atherosclerotic cardiovascular disease (ASCVD), aortic valve disease, and acute pancreatitis. With conventional lipid-lowering therapies, such as statins, many patients with genetic dyslipidemias remain inadequately controlled while other patients are unable to tolerate them, necessitating ongoing research and development of innovative therapies. Several therapeutic lipid targets-including proprotein convertase subtilisin/kexin type 9 (PCSK9), lipoprotein(a) [Lp(a)], apolipoprotein (apo) C-III (APOC3), and angiopoietin-like protein 3 (ANGPTL3)-have been identified and validated through human genetic and epidemiologic studies. Emerging ribonucleic acid (RNA) targeting and gene-editing therapies now offer the potential for durable correction of these metabolic disturbances. Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) targeting PCSK9, Lp(a), apo C-III and ANGPTL3 have shown marked efficacy in lowering atherogenic lipoproteins and triglycerides, while DNA base-editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR associated protein 9 (Cas9) and related base-editing techniques, aim to provide long-term or even permanent gene silencing to control atherogenic lipids. Together, these innovations mark a paradigm shift toward precision, gene-based lipid management, expanding therapeutic options, improving clinical outcomes, and addressing unmet medical needs in patients with severe or refractory dyslipidemias or in those unable to tolerate standard therapies. Show less

Chylomicronemia, defined by fasting triglycerides ≥10 mmol/L (≥885 mg/dL), has diverse etiologies. When clinical features such as abdominal pain, lipemia retinalis, eruptive xanthomas, hepatosplenomegaly, pancreatitis, or visibly lipemic plasma accompany the biochemical disturbance, the condition is called chylomicronemia syndrome. Subtypes include rare monogenic familial chylomicronemia syndrome (FCS), the more common multifactorial chylomicronemia syndrome (MCS), autoimmune chylomicronemia, and lipodystrophy-associated chylomicronemia. Patients are at risk for acute pancreatitis and sometimes atherosclerotic cardiovascular disease. Accurate diagnosis includes medical history, physical exam, laboratory testing (including plasma apolipoprotein B and the ratio of triglyceride to total cholesterol), clinical scoring systems, as well as selective use of genetic testing when FCS is suspected. In adults, the overwhelming majority of patients with chylomicronemia have MCS and not FCS. Treatment centers on dietary fat restriction, total alcohol avoidance, management of secondary factors, and traditional triglyceride-lowering therapies such as fibrates and omega-3 fatty acids. Acute pancreatitis management requires stabilization, analgesia, supportive care, and preventive management of hypertriglyceridemia. Emerging RNA-based therapies targeting apolipoprotein C-III (eg, volanesorsen, olezarsen, and plozasiran) offer transformative potential for FCS and for some refractory patients with other chylomicronemia subtypes. A multidisciplinary approach-integrating clinical, biochemical, and genetic assessment-guides therapy and reduces pancreatitis risk. Show less

Apolipoprotein C-III (apoC-III) has emerged as a pivotal regulator of triglyceride metabolism and a key factor in cardiovascular risk. This review explores the physiological and pathological roles of apoC-III, focusing on kinetic mechanisms, genetic data, and the therapeutic potential of targeting apoC-III. Loss-of-function mutations in APOC3 significantly lower plasma triglyceride levels and coronary heart disease risk, validating apoC-III as a therapeutic target. Kinetic studies indicate that increased hepatic secretion of apoC-III raises triglyceride levels, particularly in individuals with type 2 diabetes. Beyond lipid metabolism, apoC-III promotes lipoprotein retention and amplifies arterial inflammation. Novel inhibitors, such as antisense oligonucleotides targeting APOC3, have been shown to markedly reduce plasma apoC-III and triglyceride concentrations in both preclinical and clinical studies. Genetic and mechanistic evidence together establish the inhibition of apoC-III as a promising strategy for patients at high risk of persistent hypertriglyceridemia and cardiovascular disease. ApoC-III not only controls lipid metabolism but also exerts direct pro-atherogenic and pro-inflammatory effects, supporting its role as a multifaceted therapeutic target in cardiometabolic medicine. Show less

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools-including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors-and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as Show less

Schizophrenia is frequently comorbid with dyslipidemia and hyperglycemia. However, whether metabolic-modifying agents aggravate schizophrenia progression remains unclear. We perform a drug-target genetic association study in two independent Han Chinese schizophrenia cohorts (N = 2,111/292 for discovery/validation). Leveraging metabolic genome-wide association studies, we generate genetic risk scores (GRSs) for lipid-modifying and hypoglycemic targets. Those with higher APOC3 (inhibited by volanesorsen/olezarsen) GRS exhibit attenuated triglycerides and improvement in negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) (β = 1.23, 95% confidence interval [CI]: 0.30-2.16). Higher GCK (activated by dorzagliatin) GRS is associated with decreased glucose and less improvement across PANSS total (β = -1.70, 95% CI: -2.91-0.50), positive, negative, general subscales. Causal associations of GCK are replicated in independent validation. The effects of APOC3 and GCK on negative symptom recovery are robust in hyperlipidemic/diabetic subgroups. Genetically proxied proteomics analysis provides further functional validation for the identified target-outcome associations. Our findings suggest volanesorsen/olezarsen as potential adjunctive candidates; dorzagliatin warrants prudence in schizophrenia with metabolic disturbance. Show less

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder associated with extreme hypertriglyceridemia and high risk of acute pancreatitis. Olezarsen-an antisense oligonucleotide targeting hepatic apolipoprotein C3 (APOC3) messenger RNA-reduces triglycerides and may decrease pancreatitis risk. Olezarsen 80 mg once monthly is approved in the United States as an adjunct to diet to reduce triglycerides in adults with FCS. To assess the effect of olezarsen on all-cause healthcare resource utilization (HCRU) and overall experience of patients with genetically identified FCS enrolled in the Balance trial (NCT04568434). Prespecified exploratory endpoints included yearly all-cause hospitalization, total inpatient days, and emergency room visits for patients treated with olezarsen (80 or 50 mg) vs placebo, as well as Patient Global Impression of Change (PGIC). Ad hoc outcomes included length of hospital stay, intensive care unit (ICU) admissions, reasons for HCRU, and all-cause HCRU according to patients' history of acute pancreatitis and for individual olezarsen doses vs placebo. Treatment with olezarsen vs placebo for 1 year was associated with an 84% reduction in all-cause hospitalizations (mean rate ratio [95% CI], 0.16 [0.05, 0.50]), 6.3 fewer total inpatient days (95% CI, -11.09, -1.53), better PGIC scores, shorter length of stay, and numerically fewer ICU admissions. Acute pancreatitis was the most frequent cause of hospitalization. Reduction in all-cause inpatient service utilization was consistent for individual dose groups and in patients with a history of acute pancreatitis. In the Balance study, olezarsen reduced all-cause inpatient service utilization and improved the experience of patients with FCS. Show less

Apolipoprotein C-III (ApoC-III) amyloidosis is an extremely rare systemic amyloidosis previously reported only in humans and white lions. This report describes the first case of ApoC-III amyloidosis in an Asiatic lion (16-year-old male) that died with clinical manifestations of renal failure. Histopathological and ultrastructural examinations identified amyloid deposits predominantly at the renal corticomedullary junction. Mass spectrometry and immunohistochemistry identified ApoC-III as an amyloid precursor protein. Sequencing of the lion's APOC3 gene found no pathogenic mutations, although lion species have a unique M30V substitution compared with other Panthera species, which may predispose them to Apo-CIII amyloidosis. This first case of a non-white lion indicates that ApoC-III amyloidosis is not restricted to white lions. Show less

Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD), partly due to phosphate-induced vascular calcification. Fetuin-A stabilizes calcium-phosphate complexes into calciprotein particles (CPPs), preventing precipitation, but CPPs can mature into crystalline particles that drive calcification, particularly in CKD. In this study, we investigated whether citrate, a calcium chelator, could mitigate CPP-induced vascular calcification in vitro. Vascular smooth muscle cells (VSMCs) were incubated with CPPs containing varying citrate concentrations. We quantified calcification using calcium assays and characterized CPPs using spectrophotometry, dynamic light scattering, cryogenic transmission electron microscopy (cryo-TEM), electron diffraction (ED), Raman spectroscopy, energy dispersive X-ray spectroscopy, and mass spectrometry (MS). The highest citrate concentration, reduced calcification by 88% versus standard CPPs ( Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder marked by severe hypertriglyceridemia and characteristic clinical manifestations, particularly acute pancreatitis. Conventional triglyceride-lowering therapy is largely ineffective. Apolipoprotein (apo) C-III has emerged as a key therapeutic target to lower triglycerides in FCS. This review compares FCS with more common multifactorial chylomicronemia. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'plozasiran,' 'olezarsen,' and 'volanesorsen.' We outline traditional management strategies and their limited role in FCS and explore non-traditional therapies including orlistat, lomitapide, inhibitors of angiopoietin like protein 3 (ANGPTL3), and analogues of fibroblast growth factor 21 (FGF21). The primary focus is on RNA-based gene silencing therapeutics that target apo C-III, particularly the small interfering RNA plozasiran and the allele specific oligonucleotides volanesorsen and olezarsen, highlighting key differences in efficacy and tolerability. In a phase 3 trial of plozasiran, at 10 months, median placebo-adjusted reductions in apo C-III were approximately -90%, while TG levels were reduced up to -59%. Thus, plozasiran and alternative RNA-based therapeutics directed against APOC3 represent transformational therapies for patients with FCS and related phenotypes characterized by severe recalcitrant hypertriglyceridemia. Show less

T2DM is characterized not only by chronic hyperglycemia but by a complex disturbance in triglyceride-rich lipoprotein (TRL) metabolism. Among the resulting lipid fractions, remnant cholesterol (RC) has emerged as a potentially independent atherogenic driver that persists despite optimal low-density lipoprotein cholesterol (LDL-C) control. Growing evidence suggests that RC integrates metabolic dysregulation, insulin resistance (IR), and inflammatory signaling, thereby contributing to the "residual risk" of vascular complications in DM. To evaluate whether RC functions as an independent atherogenic lipoprotein in T2DM and to assess its clinical implications for risk prediction and therapeutic targeting. This narrative review examined relevant cohort studies, genetic analyses, mechanistic experiments, and clinical trials published in the last decade with emphasis on RC definitions, measurement approaches, associations with macrovascular and microvascular outcomes, and therapeutic modulation. RC elevation in T2DM reflects impaired TRL clearance driven by IR, hepatic VLDL overproduction, and adipose lipolysis. Across large cohorts, RC consistently predicts incident T2DM, major cardiovascular events, renal deterioration, and peripheral arterial disease independent of LDL-C, triglycerides, HbA1c, and inflammatory markers. RC trajectories and visit-to-visit variability further strengthen risk discrimination, suggesting that dynamic fluctuations reflect underlying metabolic instability. Thresholds associated with vascular injury vary across populations (≈0.56-0.80 mmol/L). Therapeutically, high-intensity statins, EPA-based therapy, and emerging APOC3/ANGPTL3 inhibitors lower RC to varying degrees, yet outcome trials targeting RC specifically remain scarce. RC represents a distinct atherogenic entity in T2DM. Its strong and independent associations with cardiovascular and renal events position it as a critical, yet underrecognized, contributor to diabetic vascular risk. Incorporating RC into routine risk assessment and exploring targeted interventions may bridge the persistent gap between LDL-C lowering and actual event reduction. Future studies should prioritize standardized measurement, mechanistic elucidation, and randomized trials directly testing whether lowering RC can modify clinical outcomes. Show less

Prostate cancer (PCa) cells are known to heavily depend on lipids to support their growth. We hypothesized that hyperlipidemic factors, for which inhibitors are already available and used to treat cardiovascular disease, would be dysregulated in metastatic PCa (mPCa). The goal of this case-control study, including 35 men per group, was to compare the levels of PCSK9, ANGPTL3, Apo CIII, leptin, and the lipid profile in patients with mPCa versus localized Gleason 8/9 PCa (lPCa) and patients at risk of developing PCa (controls). Protein levels were assessed using ELISAs, while lipids were measured using the Roche Cobas analytical platform. The following circulating analytes were higher in mPCa: triglycerides (in mmol/L; controls 1.7 ± 1.2, lPCa 1.5 ± 0.7, mPCa 2.3 ± 1.2, In this cohort of men, whole-body lipid metabolic rewiring is a feature restricted to the metastatic phase of prostate cancer, suggesting it may play a significant role in the progression toward more aggressive cancer forms. Given the availability of drugs targeting ANGPTL3 and Apo CIII, the therapeutic potential of these drugs should be evaluated in metastatic PCa. Show less

Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by severe hypertriglyceridemia and a risk of recurrent pancreatitis. Patients with biallelic pathogenic variants affecting lipoprotein lipase (LPL)-mediated triglyceride metabolism may remain refractory to conventional lipid-lowering therapies and strict dietary control, leading to recurrent critical illness and progressive multisystem complications. We report a female patient with genetically confirmed FCS and persistent triglyceride levels typically in the 4,000-5,000 mg/dL range despite adherence to diet and lipid-lowering therapy, without clear secondary contributors to severe hypertriglyceridemia. Her course included recurrent intensive care unit (ICU) admissions for hypertriglyceridemia-associated pancreatitis requiring insulin drips, with progression to chronic pancreatitis, pancreatic insufficiency requiring enzyme replacement, insulin-dependent diabetes with continuous glucose monitoring (CGM), chronic pain syndrome with opioid dependence concerns, and psychiatric comorbidity. During a hospitalization approximately 10 months prior to the most recent follow-up, the patient underwent placement of a right chest tunneled central venous catheter and initiated therapeutic plasmapheresis. She was concurrently followed by a triglyceride clinic and continued on olezarsen. At follow-up on February 25, 2025, she reported no hospitalizations since April 2024. A triglyceride value of 4,700 mg/dL was documented shortly before a scheduled plasmapheresis session. This case highlights the complexity of severe FCS when hypertriglyceridemia remains refractory to conventional management and illustrates a care pathway in which chronic outpatient plasmapheresis combined with emerging RNA-based therapy was associated with stabilization and avoidance of recurrent hospitalization. Sustained outpatient success required multidisciplinary coordination, addressing pancreatitis sequelae, glycemic management, chronic pain, psychiatric disease, and central-line monitoring. These observations are hypothesis-generating and highlight the potential role of coordinated outpatient plasmapheresis and emerging RNA-based therapies in the management of severe FCS. To our knowledge, reports describing long-term outpatient stabilization of severe FCS using combined chronic plasmapheresis and apolipoprotein C-III (APOC3)-targeted RNA therapy remain limited, and this case highlights a potential care pathway for patients with refractory disease. Show less

Hypertriglyceridemia (HTG) is a heterogeneous metabolic disorder driven by both genetic susceptibility and secondary factors. Most cases of severe HTG (triglyceride [TG] >10 mmol/L [>885 mg/dL]) have multifactorial chylomicronemia syndrome (MCS) while only a few have familial chylomicronemia syndrome (FCS), a rare autosomal recessive condition. We summarize the pathophysiology of severe HTG, emphasizing impaired intravascular lipolysis of TG-rich lipoproteins and the regulatory role of apolipoproteins (apo), particularly apo C-III. We outline features that distinguish FCS from MCS and discuss diagnostic strategies, including clinical scoring systems and targeted genetic testing. Current management approaches, including responses to conventional TG-lowering therapies and emerging biologic therapies targeting apo C-III, are examined. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'familial chylomicronemia syndrome,' 'multifactorial chylomicronemia syndrome,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'antisense oligonucleotides,' and 'apolipoprotein C-III.' Differentiating FCS from MCS is critical because RNA-based inhibition of apo C-III has transformed the therapeutic landscape for FCS patients. These agents provide substantial, durable TG lowering and meaningful reductions in pancreatitis risk, although cardiovascular benefit remains uncertain. Future efforts should focus on optimizing diagnostic pathways, assessing cardiovascular outcomes, and determining long-term safety of novel biologic therapies. Show less

Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associated with the incidence of ischemic heart disease (IHD). However, the causal association between ApoC3 and IHD development is unclear. ApoC3 expression changes were assessed in plasma from IHF patients/healthy donors and cardiac tissue from rodent models. 10-week-old male human ApoC3 transgenic (ApoC3 Overexpression of human ApoC3 in ApoC3 ApoC3 overexpression could activate cardiac TLR2/NF-κB to trigger the inflammation, oxidation, and apoptosis pathways, finally aggravating IHF in mice. Inactivation of ApoC3 could significantly alleviate IHF in hamsters. Show less

Plozasiran (Redemplo), a novel small interfering RNA (siRNA) therapeutic targeting the hepatic biosynthesis of apolipoprotein C-III (APOC3), is approved by the US FDA for treating familial chylomicronemia syndrome (FCS), a disease of rare prevalence that presents with extremely elevated levels of serum triglycerides (TG) leading to a higher risk of acute pancreatitis. Plozasiran is also in Phase 3 development to treat the broader indication of severe hypertriglyceridemia. Population pharmacodynamic (PD) analysis of plozasiran was conducted on serially measured serum APOC3 and TG levels in the FCS patients participating in the pivotal Phase 3 study by employing a cascading kinetic-PD model that described the inhibitory effect of plozasiran on the synthesis of APOC3, which in turn decreases serum TG levels. The estimated IC Show less

Vascular calcification (VC) is prevalent in patients with chronic renal failure (CRF), and it is closely related to the morbidity and mortality of cardiovascular diseases; however, no medical treatments are available for this condition. Recent clinical studies have shown that plasma apolipoprotein C3 (ApoC3) levels are positively correlated with VC. However, whether ApoC3 is involved in VC remains unclear. Sections of calcified renal arteries from CRF patients were immunostained to measure calcium deposition and ApoC3 expression. VC was induced in ApoC3 transgenic (Tg) and knockout (KO) mice by both 5/6 nephrectomy and vitamin D ApoC3 expression levels were increased in calcified arteries from mice and patients with CRF. ApoC3 overexpression exacerbated calcium deposition in the calcified aortas from Tg mice in vivo, and in calcified aortic rings of Tg mice ex vivo and VSMCs infected by adenovirus of ApoC3 in vitro. Consistently with these findings, ApoC3 deficiency alleviated these effects. Furthermore, ApoC3 overexpression increased ferroptosis in calcified aortas and VSMCs, whereas ApoC3 deficiency suppressed ferroptosis. Further investigation revealed that ApoC3 inhibited the AMPK/NRF2 signaling pathway through toll-like receptor 2 (TLR2) in calcified VSMCs, downregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), subsequently increased lipid peroxidation and promoted ferroptosis, ultimately exacerbating calcification in the VSMCs. Furthermore, we found that knockdown of ApoC3 by siRNA remarkably attenuated calcification of renal arterial rings in humans. We demonstrated that ApoC3 exacerbated VC and increased the osteogenic transdifferentiation in VSMCs by increasing ferroptosis. ApoC3 might be a potential target for VC treatment. Show less

Obesity is a well-documented cardiovascular risk factor. Here, we sought to investigate whether obesity causes subclinical cardiac remodeling and heart failure (HF), and if so, to perform a systematic scan of the plasma protein for novel drug targets. We leveraged visceral adipose tissue (VAT), waist circumference (WC), and waist-to-hip ratio (WHR)-all adjusted for body mass index (BMI)-as indicators of obesity. Two-sample Mendelian randomization (MR) analyses were used to estimate the independent, causal effects of obesity on cardiovascular magnetic resonance (CMR)-derived cardiac traits and HF risk. Mediation analyses followed by druggability assessment were conducted to identify promising protein targets for therapeutic translation. Genetically determined VATadjBMI, WCadjBMI, and WHRadjBMI presented broad causal associations with alterations of distinct cardiac phenotypes, most of which remained significant after controlling for obesity-induced cardiometabolic risk factors, including hypertension, type 2 diabetes, and adverse lipid profiles. By contrast, WHRadjBMI is the only independent causal predictor for HF risk. Of 142 proteins with mediating effects, scavenger receptor class A member 5 (SCARA5), membrane cofactor protein (CD46), and alpha-1-antichymotrypsin (SERPINA3) may contribute to the early-stage adverse cardiovascular effect of obesity, whereas apolipoprotein C-III (APOC3), mitochondrial aldehyde dehydrogenase 2 (ALDH2), and chordin-like protein 2 (CHRDL2) may further promote the development of obesity-driven HF. Medications targeted at these candidate proteins are either approved or under evaluation in clinical trials. Our MR findings provided genetic evidence for the direct, causal associations of obesity with cardiac remodeling and HF, while also outlining druggable proteins as promising therapeutic targets. Show less

Small dense low-density lipoprotein (sdLDL) is a highly atherogenic LDL subclass associated with cardiovascular disease (CVD). While type 1 diabetes confers increased cardiovascular risk despite adequate glycemic control, the role of sdLDL and its regulators remains unclear. In this cross-sectional observational study, plasma from 69 individuals with long-standing type 1 diabetes and 24 healthy controls was analyzed. sdLDL-cholesterol (sdLDL-C) concentration, sdLDL-C/LDL-cholesterol ratio, LDL size and subclasses were assessed using homogeneous assays, NMR spectroscopy, and gradient gel electrophoresis. Apolipoprotein C3 (ApoC3), hepatic lipase (HL), endothelial lipase (EL), and cholesteryl ester transfer protein (CETP) activity were measured by immunoturbidimetric, ELISA and functional assays. Despite adequate glycemic control (mean HbA1c 7.6% [60 mmol/mol]) and near-normal lipid levels, individuals with type 1 diabetes had significantly higher sdLDL-C (0.56 ± 0.28 mmol/L vs 0.43 ± 0.26 mmol/L), increased sdLDL-C/LDL-cholesterol ratio (0.20 ± 0.08 vs 0.12 ± 0.06) and smaller LDL particle size (26.32 ± 1.08 nm vs 26.81 ± 0.68 nm) compared with controls. ApoC3 and HL mass/activity were significantly increased (8.67 ± 3.22 mg/dL vs 6.53 ± 2.42; 46.60 ± 16.12 ng/mL vs 15.45 ± 7.40 ng/mL and 1.03 ± 0.24 U/mL vs 0.89 ± 0.23 U/mL; respectively), CETP activity significantly reduced (808.8 ± 197.0 pmol/mL/h vs 929.7 ± 149.6 pmol/mL/h), and endothelial lipase levels unchanged. sdLDL-C positively correlated with ApoC3 (r = 0.7517) and inversely with CETP activity (r = -0.2682). Long-standing type 1 diabetes with adequate glycemic control is associated with an atherogenic sdLDL profile despite near-normal conventional lipid levels. This first multi-method characterization study of sdLDL in type 1 diabetes highlights the contribution of ApoC3, CETP and HL to sdLDL-C enrichment and suggests that direct assessment of sdLDL may improve cardiovascular risk stratification. Show less

Canine hepatocellular carcinoma (HCC) requires further molecular characterization to identify diagnostic and therapeutic targets, and to establish whether dogs with this condition can model the human disease. Accordingly, we aimed to identify differentially expressed genes (DEGs) in canine HCC and evaluate cross-species transcriptomic dysregulation in canine and human HCC. Liver tissue samples from three dogs with HCC and three healthy dogs were subjected to next-generation sequencing, followed by RT-qPCR validation. Identified DEGs were then targeted in bioinformatics analyses (pathway enrichment, protein-protein interaction network, and hub gene analyses) for molecular characterization and comparison with human HCC datasets. We identified 975 DEGs (upregulated: 604; and downregulated: 371). Extracellular matrix-receptor interaction, focal adhesion, cell adhesion molecule, PI3K/Akt signaling, and cytokine/chemokine-related pathways were enriched. C1R, APOC3, C1QA, APOA1, C1QB, ACTG1, C1QC, CRP, ANXA5, and ANXA2 were identified as hub genes. Canine and human HCCs share 118 DEGs, highlighting conserved alterations in metabolic pathways, PI3K-Akt signaling, focal adhesion, and PPAR signaling pathways. Based on human HCC data, SPP1, NQO1, RRM2, APOA1, APOC3, ALDOB, and IGF1 were identified as prognosticators indicating poor overall survival. This study presents the first cross-species transcriptomic analysis of canine HCC, revealing significant molecular resemblances to human HCC, indicating it may be a promising comparative model for studying tumor biology, drug responses, and novel therapeutic interventions. Show less

In familial chylomicronemia syndrome (FCS), a rare lipid disorder, triglycerides rise to extremely high levels because of the inability to utilize lipoprotein lipase (LPL) for fat metabolism. Traditional triglyceride-lowering medications are ineffective, leaving patients dependent on strict low-fat diets. This review examines emerging non-LPL-based therapies for FCS. This narrative review assessed therapeutic strategies targeting key regulators of triglyceride metabolism, including apolipoprotein C-III (APOC3) and angiopoietin-like protein 3 (ANGPTL3), in both animal and human studies. Investigational approaches included monoclonal antibodies, RNA-based therapies, gene therapy modalities, genome editing platforms, and plasmapheresis. Olezarsen effectively lowers triglycerides with greater safety than older options. Other agents, such as ANGPTL3 inhibitors and RNA interference therapies, also reduce lipids and provide additional treatment options. Gene therapy and clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 approaches are expected to become available in the near future, while plasmapheresis remains an intervention for acute pancreatitis. Innovative therapies targeting APOC3, ANGPTL3, or liver-specific genes are transforming the management of FCS. These advances not only address this rare disorder but also offer insights into treating triglyceride-related cardiovascular risk and lipid abnormalities. Although some uncertainties remain, the outlook for FCS therapy appears highly promising. Show less

Sex hormones, particularly testosterone, modulate immune function during critical illness, and patients with septic shock frequently exhibit hypotestosteronemia. However, the causal relationship between testosterone and outcomes remains unclear owing to the confounding effects of illness-related changes in hormone levels during acute illness. We investigated 469 patients with septic shock in multicenter ICUs using a testosterone polygenic score (PGS) derived from genome-wide association studies combined with two-sample Mendelian randomization to establish causal relationships independent of confounding factors. Cox proportional hazards regression was performed to assess the association with 28-day mortality. Additionally, we evaluated whether apolipoprotein C3 (ApoC3) levels modified the protective effects of testosterone using interaction models and the likelihood ratio test. Higher genetically predicted testosterone levels were significantly associated with improved 28-day survival (adjusted hazard ratio [HR] 0.72 per 1-standard deviation increase in PGS; Genetically determined higher testosterone levels are causally associated with improved survival in patients with septic shock, particularly in men and in those with lipid dysmetabolism. These findings identify testosterone as a potential therapeutic target and highlight lipid metabolism as a key modifier of the protective effects of testosterone against septic shock, warranting the investigation of testosterone-based interventions in future clinical trials. The online version contains supplementary material available at 10.1186/s13054-026-05860-x. Show less

Apolipoprotein C3 (apoC3) circulates primarily on triglyceride-rich lipoproteins and promotes atherosclerosis by fostering lipidemia and inflammation. Thus, apoC3 represents an important cardiovascular risk factor and is associated with cardiovascular events and mortality. Due to their dual nature as hemostatic and immunomodulatory effector cells, platelets play an important role in the development and progression of atherosclerosis and are responsible for thrombotic/thromboembolic events upon plaque rupture. We aimed to elucidate the impact of apoC3 on prothrombotic platelet functions. Platelets were isolated from healthy volunteers and the effect of apoC3 on their activation and aggregation was assessed by flow cytometry, ELISA, and light transmission and multiple electrode aggregometry. Platelet spreading and cytoskeletal remodeling were examined by immunofluorescence microscopy. In vivo relevance was confirmed in a murine model of FeCl ApoC3 strongly reduced platelet aggregation independently of the presence of plasma or other blood cells and impaired both α We identified apoC3 as lipoprotein-derived inhibitor of prothrombotic platelet functions, mediating antiaggregatory effects, likely via modulating AKT and VASP signaling and interfering with actin cytoskeleton remodeling to impair lamellipodia formation. Thus, apoC3 may counterbalance its proatherogenic properties on lipid metabolism and inflammation by dampening thrombotic risk in hyperlipidemia. Show less

Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanisms. Using quantitative proteomic analysis on the plasma of bacteraemic participants, we demonstrate that wild-type toxigenic Salmonella induced secretion of lysozyme (LYZ) and apolipoprotein C3 (APOC3). Recombinant typhoid toxin or Salmonella infection recapitulated LYZ and APOC3 secretion in cultured cells, which involved ATM/ATR-dependent DDRs and confirmed observations in typhoid fever. LYZ caused spheroplast formation, inhibited the Salmonella type 3 secretion system, and intracellular infections. LYZ expression was regulated by p53 in a cell type-specific manner and driven by mitochondrial oxidative stress that caused nuclear DDRs and p53-mediated senescence responses. Addition of LYZ inhibited oxidative DNA damage and resulting senescence responses caused by typhoid toxin. Our findings may indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever. Show less