The living record of
peptide science.

Zinc Coordination by Thymosin β4: Structural Determinants and Functional Implications.

Int J Mol Sci

Joanna Izabela Lachowicz, Terenzio Congiu, Andrea Salis +1 more

Thymosin β4 (Tβ4) is a highly acidic, intrinsically disordered 43-amino-acid peptide with diverse biological functions, yet its interactions with metal ions remain poorly understood. In this study, we provide the first experimental demonstration that Tβ4 forms discrete Zn2+-bound adducts and undergoes Zn2+-induced aggregation under physiological pH conditions. Combining zeta potential analysis, dynamic light scattering (DLS), electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscopy with elemental mapping (SEM/EDS), we show that Zn(II) binding progressively neutralizes Tβ4's negative surface charge and triggers a sharp aggregation transition. ESI-MS unambiguously identifies Tβ4/Zn(II) complexes of peptide-to-zinc molar ratio 1:3, while DLS and SEM reveal the formation of compact, low-solubility supramolecular assemblies. NMR measurements support a metal-induced aggregation, confirming the absence of folding upon Zn(II) binding. By quantitatively comparing the experimentally determined critical aggregation concentration with physiologically observed extracellular Zn(II) ranges, we demonstrate that aggregation is unlikely in plasma or basal interstitial environments but may become feasible in Zn-rich microdomains, such as the synaptic cleft, where transient Zn(II) levels can exceed 1 μM. These findings introduce a previously unrecognized dimension of Tβ4 chemistry and suggest that a Zn(II)-mediated supramolecular assembly of Tβ4 could influence peptide behavior in neurological or inflammatory conditions characterized by elevated extracellular Zn(II). This work establishes a foundational biochemical framework for future studies aimed at elucidating the biological implications of Tβ4/Zn(II) complexation and aggregation in vivo.

Bergenin Suppresses Glycolysis and Malignant Progression in Breast Cancer via the IGF1R-MAPK Signaling Pathway.

Ann Clin Lab Sci

Minhui Fan, Qingyu Li, Renya Shuai +2 more

This study endeavors to unravel the effects and mechanisms of bergenin (Ber) in suppressing breast cancer (BC) progression through modulating the IGF1R-MAPK signaling pathway, using an integrative approach combining network pharmacology and bioinformatics.

Boerhaave's syndrome associated with glucagon-like peptide-1 receptor agonist use: a case report.

J Cardiothorac Surg

Jason M Aubrey, Chance Benner, Geoffrey T Lam

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes and weight loss, with well known gastrointestinal side effects including nausea, vomiting, and delayed gastric emptying. While mucosal injuries such as Mallory Weiss tears have been reported, full thickness esophageal perforation has not previously been described. We report the first documented case of Boerhaave's syndrome associated with GLP-1 RA use, highlighting the potential for rare but life threatening complications following abrupt reinitiation at high doses.

Evidence-informed guidance for the clinical use of oral semaglutide in obesity management.

Postgrad Med

Domenica Rubino, Sean Wharton, Michael G Knight +1 more

Oral semaglutide, the first oral glucagon-like peptide-1 (GLP-1) receptor agonist therapy approved for the treatment of type 2 diabetes, is now approved for obesity management and cardiovascular risk reduction in adults, demonstrating weight loss comparable to that of subcutaneous GLP-1 therapies, alongside improvements in cardiometabolic risk factors. The availability of oral semaglutide for the treatment of obesity provides healthcare professionals with additional opportunities to individualize therapy based on patient preferences, lifestyle, and clinical circumstances. However, the oral semaglutide formulation requires specific administration conditions to optimize absorption and effectiveness. Notably, oral semaglutide tablets should be taken first thing in the morning on an empty stomach with no more than half a glass of plain water (up to 120 mL or 4 fl oz), followed by 30 min before eating food, drinking additional fluids, or ingesting other oral medications. Person-centered clinical discussions between healthcare professionals (HCPs) and patients prior to treatment initiation are important to ensure patients understand administration requirements and why they are necessary, establish realistic expectations for obesity treatment targets, and cover approaches to maintain adherence. HCP-patient consultations should also include discussion of strategies to help patients minimize, prepare for, and manage adverse events. In this article, we provide practical guidance for incorporating oral semaglutide into obesity management, drawing on evidence from clinical trials, including the OASIS 4 trial, and the authors' clinical insights.

Neurovascular unit dysfunction in vascular cognitive impairment: Mechanisms, biomarkers, and translational strategies.

Exp Neurol

Christina Hoyer-Kimura, Meredith Hay

Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous spectrum of cognitive disorders driven by cerebrovascular pathology and represents a major contributor to late-life cognitive decline. VCID is highly prevalent and frequently coexists with Alzheimer's disease pathology. Despite this, it remains poorly defined in clinical practice and lacks approved disease-modifying therapies. Therapeutic development has been hindered by biological heterogeneity, challenges in patient stratification, and a historical emphasis on neurodegenerative targets that inadequately address vascular mechanisms. Increasing evidence implicates dysfunction of the neurovascular unit-including small vessel disease, chronic hypoperfusion, blood-brain barrier disruption, and neuroinflammation-as a central driver of vascular-mediated cognitive impairment and a unifying therapeutic target across diverse VCID phenotypes. In this review, we synthesize current understanding of VCID pathobiology with a focus on neurovascular unit dysfunction and emerging mechanism-based strategies aimed at restoring vascular and neurovascular homeostasis. We further examine translational considerations for targeting neurovascular signaling pathways, including endothelial stabilization, modulation of vascular inflammation, and preservation of blood-brain barrier integrity. As an illustrative example, we discuss preclinical evidence supporting Mas receptor agonism, including the glycosylated angiotensin-(1-7) analogue PNA5, as a potential approach to address vascular-mediated cognitive impairment. Finally, we explore implications for biomarker selection, patient enrichment, and early clinical trial design. Together, this framework highlights neurovascular dysfunction as a tractable therapeutic target in VCID and underscores the need for mechanism-driven approaches to address a substantial unmet clinical need.

Syringin Protects Against Doxorubicin-Induced Cardiotoxicity via Apelinr-Dependent Activation of the Nuclear Factor-Erythroid 2-Related Factor 2/Heme Oxygenase-1 Antioxidant Pathway.

Phytother Res

Yujiang Li, Ting Wang, Ming Shen +10 more

Cardiotoxicity induced by the chemotherapeutic agent Doxorubicin (Dox) is a major clinical challenge, primarily mediated by overwhelming oxidative stress. While Syringin (Syr) is known for its antioxidant potential, its efficacy and mechanism in the context of Dox-induced cardiotoxicity are not well defined. This study aimed to assess the therapeutic potential of Syr in alleviating Dox-induced cardiac injury and to elucidate its underlying molecular mechanism. The cardioprotective effect of Syr was evaluated in a Dox-induced mouse model of cardiotoxicity and in primary cardiomyocytes, with pravastatin (Prv, 10 mg/kg) serving as the positive control in the Syr dose-finding experiment. Cardiac function and myocardial strain were measured by advanced echocardiography using wall-tracking and speckle-tracking analyses. Network pharmacology was applied to identify downstream signaling pathways and molecular targets of Syr. Myocardial atrophy, antioxidant proteins, and oxidative stress markers were assessed by histology, Western blotting, and qRT-PCR. To validate the key molecular target, in vivo siRNA-mediated knockdown of the apelin receptor (APJ) was performed. Syr treatment significantly attenuated myocardial atrophy and suppressed oxidative stress. Syr also increased APJ expression, activated mechanosensitive PI3K/AKT phosphorylation, and restored fibroblast growth factor 21 (FGF21) homeostasis, thereby improving myocardial circumferential and longitudinal strain. Mechanistically, APJ silencing blunted Syr's ability to upregulate antioxidant proteins in Dox-exposed cardiomyocytes, and the benefits of FGF21 overexpression were lost. Consistently, APJ knockdown abolished Syr's protection against Dox-induced cardiotoxicity in vivo, eliminating its improvements in cardiac function and myocardial strain. Our study first demonstrates that Syr protects against Dox-induced cardiotoxicity by restoring the APJ/PI3K/AKT signaling axis, which subsequently enhances the nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) antioxidant response and maintains FGF21 homeostasis. These findings identify Syr as a promising natural compound for mitigating chemotherapy-induced cardiotoxicity and highlight the APJ as a novel therapeutic target.

Screening for HFpEF in pacemaker patients: Study design and protocol of the PM-HFpEF study.

PLoS One

Elisabeth Santos, Rafael Teixeira, João Almeida +11 more

Heart failure with preserved ejection fraction (HFpEF) is common in older multimorbid patients and is associated with substantial morbidity and mortality. Pacemaker (PM) patients may be particularly vulnerable given the clustering of conventional HFpEF risk factors and the hemodynamic effects of long-term right ventricular pacing. Nevertheless, HFpEF is rarely systematically assessed in device clinics.

sweelin®, a novel sweet protein, does not affect blood glucose and insulin levels - a double-blind, crossover, randomized study.

Food Chem

Yael Lifshitz, Rotem Saban, Shira Paz +5 more

A novel hyper-sweet protein, sweelin®, enables sugar reduction without compromising taste. This double-blind, randomized, crossover study evaluated the effect of sweelin® on blood glucose, insulin and GLP-1 levels compared to stevia and dextrose in healthy adults. In this study, subjects consumed sweelin® (0.051 g), stevia Reb-M (0.225 g) or dextrose (75 g) in beverages matched for sweetness levels. Blood samples were collected at baseline and during 120-min post consumption. Each participant (n = 19) consumed each of the three beverages in a randomized order. At every time point after consumption, as well as iAUC, glucose and insulin levels were significantly lower following sweelin® consumption compared to dextrose (p < 0.0001), and not different from stevia. Overall, the findings indicate that sweelin®, is well tolerated and does not increase blood glucose, insulin or GLP-1 levels in healthy individuals, and suggest that sweelin® may serve as a metabolically neutral alternative for individuals seeking to reduce sugar intake. This trial was registered at clinicaltrials.gov (identifier code: NCT06520293).

Structural insights into histone mimicry by the small hepatitis delta antigen.

J Biol Chem

Haiyun Hu, Mengjiao Lv, Xiaohui Wang +11 more

Hepatitis delta virus (HDV) is a satellite RNA virus that requires hepatitis B virus (HBV) for propagation but replicates its genome independently in the nucleus. The small form of the hepatitis delta antigen (S-HDAg) is essential for replication and is regulated by post-translational modifications. Acetylation at lysine 72 (K72ac) enables S-HDAg to interact with the bromodomain (BRD) of the host chromatin remodeler bromodomain adjacent to zinc finger domain protein 2B (BAZ2B) to promote viral replication. However, the structural basis for this interaction has remained elusive. Here, we provide structural and biophysical insights into this interaction through quantitative binding assays and X-ray crystallography. Isothermal titration calorimetry revealed that BRDs of BAZ2B and its close homolog BAZ2A bind to the viral peptide weakly, with BAZ2A-BRD exhibiting a modestly higher affinity. The crystal structure of BAZ2A-BRD in complex with the S-HDAg-K72ac peptide demonstrates an inverted binding orientation relative to canonical histone ligands, rationalizing the weak interaction. Mutagenesis studies confirmed the critical binding interface both in vitro and in cells. These findings elucidate the molecular mechanism by which HDV co-opts host BAZ2 bromodomains via a unique, weak-affinity interaction, providing a structural framework for understanding viral replication.

LRBA regulates actin cytoskeleton dynamics through NMIIA during B cell immune responses.

EMBO Rep

Elena Sindram, Juan Eduardo Montero-Hernández, Quentin Frenger +16 more

Patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency typically suffer from severe B cell dysfunction. However, the underlying mechanisms remain incompletely understood. In this study, we identify non-muscle myosin IIA (NMIIA) as an interaction partner of LRBA in B cells, and uncover a role for LRBA in regulating actin cytoskeleton dynamics during B cell activation. LRBA-deficient B cells exhibit abnormal migration, impaired F-actin polymerization, and reduced B cell receptor signalling and polarization upon activation. In addition, LRBA deficiency severely disrupts immune synapse formation as evidenced by diminished central SMAC formation, reduced microtubule organizing center translocation and disrupted BCR and lysosome polarization. Consistent with these defects, internalization of the BCR-antigen complex is also impaired. Mechanistically, NMIIA activation, assessed by myosin light chain (MLC) phosphorylation, is reduced in LRBA-deficient cells. In addition, LRBA co-localizes with active NMIIA during both migration and immune synapse formation. Collectively, our findings establish LRBA as an important regulator of cytoskeleton dynamics during B cell activation, which may contribute to the defective humoral immunity observed in LRBA-deficient patients.

GLP-1 agonist and neuroprotection in Stroke and Parkinson's disease: A systematic review.

Dis Mon

Drashti S Parekh, Dastan Kudaiarov, Pugazhendi Inban +3 more

Glucagon-like peptide-1 receptor agonists have been shown to have neuroprotective effects in metabolic diseases, but their application in neurodegenerative diseases (stroke and Parkinson's disease) has not been adequately studied.

Author Correction: Exercise alleviates cognitive dysfunction in Alzheimer's disease mice via skeletal muscle-derived extracellular vesicles that enhance plaque clearance by microglia.

Nat Aging

Jiaquan Lin, Xiaoyan Shao, Tianshu Shi +21 more

Cost-effectiveness of iGlarLixi vs. IDegAsp in individuals with type 2 diabetes: a BRAVO model-based evaluation.

Front Public Health

Jiali Qin, Man Tang, Xiaomei Wang +5 more

This study aimed to evaluate the long-term cost-effectiveness of insulin glargine/lixisenatide injection (iGlarLixi) vs. insulin degludec/insulin aspart (IDegAsp) in individuals with poorly controlled type 2 diabetes in China.

Restoring Satiety After GLP-1/GIP Pharmacotherapy: Metabolic Stability, Diet Quality, and the Gut Microbiota.

Int J Mol Sci

Lidia Lasik, Natalia Ukleja-Sokołowska

GLP-1 receptor agonists and dual GLP-1/GIP agonists have significantly transformed the treatment of obesity, enabling clinically meaningful weight reduction and improvements in cardiometabolic parameters. However, clinical trial data indicate that cessation of therapy is associated with biologically driven weight regain and a partial loss of metabolic benefits. This phenomenon underscores the chronic nature of obesity and the limited durability of effects achieved through pharmacotherapy alone. Nevertheless, structured clinical frameworks describing how to maintain satiety and metabolic stability after GLP-1/GIP dose reduction or discontinuation remain limited. The aim of this narrative review is to discuss the mechanisms underlying weight regain following dose reduction or discontinuation of GLP-1/GIP pharmacotherapy and to present strategies supporting long-term metabolic stabilisation. Weight regain is driven in part by persistent metabolic adaptations, including a reduction in resting energy expenditure (adaptive thermogenesis), alterations in the hunger-satiety axis (increased ghrelin, reduced leptin signalling), and potentially incomplete restoration of adipose tissue and liver-related metabolic function, although direct evidence in this specific setting remains limited. Weight loss is often accompanied by a reduction in fat-free mass, which further lowers energy expenditure and increases susceptibility to a positive energy balance after treatment cessation. It remains unclear whether pharmacological suppression of appetite results in sustained normalisation of endogenous satiety regulation after treatment cessation, and its effects on gut microbiota function remain uncertain. In clinical practice, key priorities include preserving muscle mass (adequate protein intake, resistance training), maintaining dietary nutrient density, stabilising postprandial glycaemia, and ensuring sufficient intake of fermentable fibre to support short-chain fatty acid production and gut-brain signalling. GLP-1/GIP pharmacotherapy should be viewed as a component of an integrated model of obesity treatment. We propose that long-term weight stabilisation may require a transition from pharmacologically induced satiety to satiety supported by diet quality, preserved fat-free mass, and metabolic stability. Further research is needed to define optimal post-treatment strategies and to identify patients in whom therapy can be safely reduced or discontinued. This transition should be regarded as a conceptual framework and forward-looking hypothesis requiring validation in prospective studies.

Mice lacking β-arrestin-2 in melanocortin 4 receptor-expressing neurons show marked metabolic deficits.

JCI Insight

Misbah Rashid, Lei Wang, Zhenzhong Cui +7 more

Hypothalamic melanocortin 4 receptors (MC4Rs) play a central role in regulating food intake and energy homeostasis. In fact, inactivating mutations in the MC4R gene are the most common form of monogenic obesity. Agonist activation of MC4Rs reduces food intake by modulating hypothalamic signaling circuits. Thus, a detailed understanding of the signaling pathways that regulate MC4R activity is of considerable translational relevance. Ligand-activated MC4Rs not only interact with heterotrimeric G proteins but also can recruit β-arrestin-2 (barr2) to the receptor. The potential functional role of barr2 in regulating the anorectic effects of MC4R signaling remains unexplored. In the present study, we used mutant mouse models to demonstrate MC4R-mediated activation of barr2/ERK signaling in MC4R neurons of the paraventricular nucleus leads to reduced food intake. We also found the appetite-suppressing effect of setmelanotide, an MC4R agonist FDA approved for the treatment of certain types of obesity, requires the presence of barr2 in MC4R-containing neurons. These data suggest that MC4R agonists able to promote MC4R/barr2 interactions with high efficacy may become useful as appetite-suppressing drugs.

Nucleobindin-derived peptides and stress regulation in vertebrates.

Gen Comp Endocrinol

Paalki Sethi, Atefeh Nasri, Suraj Unniappan

Stress response entails a complex array of interactions between the neuroendocrine system and physiological and behavioral effects. When a sensory stimulus is perceived as stressful, the brain triggers a response controlled by two key neuroendocrine systems: the sympathetic pathways for the "fight or flight" response, and the hypothalamus-pituitary-adrenal (HPA) axis, for a long-term stress response. Growing evidence suggests that nucleobindin (Nucb)-derived peptides nesfatin-1 and nesfatin-1-like peptide (NLP), two anorexigens and metabolic regulators, are also involved in stress regulation. Nesfatin-1 stimulates corticotropin-releasing hormone (CRH) in the hypothalamus to induce stress and satiety. Nesfatin-1 and NLP activate the stress axis, stimulating adrenocorticotropic hormone (ACTH) synthesis and modulating cortisol synthesis. Nesfatin-1 elicits stress behavior, such as anxiety and depression. Nesfatin-1 and NLP regulate both stress and metabolism, suggesting their role in interlinking these processes. This review discusses the involvement of nesfatin-1 and NLP in stress-related pathways in vertebrates, their mechanism of action, as well as existing knowledge gaps that warrant further research.

BPC-157 and Its Novel Hybrid Analogs as Inhibitors of Acetylcholinesterase.

Int J Mol Sci

Juliana Jelińska, Michalina Józwiak, Łukasz Szeleszczuk +5 more

Acetylcholinesterase (AChE) inhibition remains a key therapeutic strategy in the management of neurodegenerative disorders such as Alzheimer's disease. In this study, the inhibitory potential of the gastric pentadecapeptide BPC-157 and two newly designed hybrid analogs, CIARA-1 and CIARA-2, was investigated for the first time. The hybrid peptides were rationally designed by combining a BPC-157-derived fragment with an arginine-containing C-terminal sequence to enhance interactions with the enzyme's active and peripheral binding sites. Enzyme kinetics were evaluated using a modified Ellman assay, and inhibition parameters were determined through Lineweaver-Burk analysis. All tested compounds exhibited a competitive mechanism of inhibition, as evidenced by increased Michaelis-Menten constant (Km) values with unchanged maximum velocity (Vmax), indicating competition with the substrate at the catalytic site of AChE. Among the tested compounds, CIARA-1 demonstrated the highest inhibitory potency, reflected by the lowest inhibition constant (Ki = 0.24 mM) and IC50 value (2.52 mM), followed by CIARA-2 (Ki = 0.29 mM; IC50 = 2.73 mM) and BPC-157 (Ki = 0.48 mM; IC50 = 2.80 mM). These findings were consistent with molecular modeling predictions, supporting stronger binding interactions for CIARA-1. Despite significantly lower potency compared to clinically used AChE inhibitors, the studied peptides represent a promising scaffold for further optimization. Overall, this work demonstrates that BPC-157 and its hybrid analogs act as reversible competitive AChE inhibitors, with enhanced activity observed for structurally modified derivatives. The results highlight the potential of peptide-based hybrid molecules as multifunctional candidates in the development of novel therapeutics targeting cholinergic dysfunction.

Reparative Outcomes in Corneal Infection: Linking Adjunctive Tβ4 Treatment to Nerve Regeneration and Visual Function.

Invest Ophthalmol Vis Sci

Abdul Shukkur Ebrahim, Li Liu, Thomas W Carion +7 more

Previous studies have shown that adjunctive thymosin beta-4 (Tβ4) with ciprofloxacin reduces bacterial keratitis severity, enhances wound repair, and promotes a return to homeostasis. However, its impact on corneal nerves and visual function, two critical but often overlooked determinants of long-term outcomes, remains unexplored. The present study addresses this gap by evaluating whether adjunctive Tβ4 supports nerve regeneration and restores visual function after infection.

Inhibition of IGF1R in Early MMTV-Wnt1 Mammary Tumors: A Transcriptomic Analysis.

Cancers (Basel)

Joseph J Bulatowicz, Alexander Lemenze, Elvan Dogan +4 more

Background: The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase whose both overexpression and underexpression have been implicated in the initiation and progression of breast tumorigenesis. The mechanism through which underexpression of the receptor contributes to a more aggressive phenotype is currently less understood. Methods: Through the expression of a dominant-negative IGF1R, we studied the phenotypic effects of receptor inhibition on early MMTV-Wnt1 mouse mammary tumors. Utilizing histopathological techniques and single-cell RNA-sequencing, we explored cellular heterogeneity and transcriptional alterations that occur as a result of IGF1R inhibition. Results: Examination of primary tumors failed to reveal obvious differences in tissue architecture or expression of differentiation markers with IGF1R inhibition. Both cohorts of tumors produced metastatic lesions in the lung. Single-cell RNA-sequencing identified previously unknown epithelial subpopulations that were present in both tumor types. In tumors with inhibited IGF1R, a previously undescribed epithelial population marked by expression of both Krt14 and Krt6a was identified, transcriptionally distinct from its MMTV-Wnt1 counterpart, and present in the smallest lung metastases. In human breast cancer patients, expression levels of KRT14 and KRT6A negatively correlated with expression of IGF1R. Conclusions: Inhibition of the IGF1R in a mouse model of basal-like breast cancer produces transcriptionally distinct Krt6a+/Krt14+ epithelial cells, which are present in the smallest metastatic lesions identified in the lung. Expression of genes associated with this population may potentially be effective biomarkers of metastatic capacity in basal-like breast tumors with low levels of IGF1R expression.

Genetic Variability in the IGF-1 Axis Modulates Cancer-Associated Cachexia and Prognosis.

Cancers (Basel)

Mariana Moreira Pires, Inês Guerra de Melo, Ana Carolina Leão Silva +7 more

Background: Cancer-associated cachexia (CAC) is a multifactorial syndrome driven by a profound metabolic and inflammatory dysregulation. Due to the central role of the insulin-like growth factor 1 (IGF-1) pathway in regulating muscle mass, energy metabolism, and inflammation, this study evaluated the relevance of five IGF-1 axis-related single-nucleotide polymorphisms (SNPs), namely IGF1 rs6220, insulin-like growth factor 1 receptor (IGF1R) rs2016347 and rs2684788, growth hormone receptor (GHR) rs6873545, and insulin receptor substrate 1 (IRS1) rs1801278. Methods: The impact of these variants on CAC onset and overall survival (OS) was assessed in a cohort of 140 cancer patients. Results: While overall-cohort analyses did not reach statistical significance, exploratory analyses suggested potential associations between the IGF1 rs6220 GG and GHR rs6873545 CC genotypes and increased CAC risk in male patients. A trend for higher CAC prevalence was also noted in younger patients (<63 years) with the rs6873545 CC genotype. For pre-CAC and CAC patients, exploratory subgroup analyses on patients' OS were conducted following no significant results in the overall cohort. Among older patients and those with high prognostic nutritional index (PNI; >44.2), the IGF1 rs6220 G allele was associated with longer OS. Conversely, the IGF1R rs2016347 G allele and rs2684788 T allele were linked to poorer OS across multiple pre-CAC and CAC subgroups. The effects of GHR rs6873545 varied across subgroups, suggesting context-dependent activity. Conclusions: This study highlights the functional heterogeneity of IGF-1 axis-related genetic variants, indicating potential to serve as predictors of CAC. Given the exploratory nature of these findings, validation in larger cohorts is required to confirm the associations found.