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peptide science.

Thyroid crisis following painless thyroiditis initially diagnosed as syndrome of inappropriate antidiuresis.

JCEM Case Rep

Miki Hamashoji, Chikayo Iwaya, Makito Tanabe +3 more

Painless thyroiditis is a destructive disorder associated with immune dysregulation. Although an abrupt reduction in corticosteroid activity has been implicated, the precipitating role of endogenous adrenal insufficiency remains unclear. A 66-year-old woman was admitted to a referring hospital with anorexia, vomiting, and hyponatremia and was diagnosed with syndrome of inappropriate antidiuresis (SIAD). Despite correction of serum sodium levels, anorexia persisted. Two months later, she developed fever, tachycardia, impaired consciousness, and severe hypercalcemia and was transferred to our institution. Laboratory evaluation revealed marked thyrotoxicosis with suppressed thyroid-stimulating hormone and elevated free thyroxine levels, along with inappropriately low adrenocorticotropic hormone (ACTH) and cortisol levels. The patient met the diagnostic criteria for thyroid crisis. Thyroid antibody testing and imaging findings were consistent with painless thyroiditis. Secondary adrenal insufficiency was confirmed by a blunted cortisol response to a rapid ACTH stimulation test. Treatment with intravenous hydrocortisone and empiric potassium iodide resulted in rapid clinical improvement. This case suggests an association between unrecognized secondary adrenal insufficiency initially diagnosed as SIAD and the subsequent occurrence of painless thyroiditis and thyroid crisis. Evaluation of adrenal function should be considered in patients with hyponatremia and thyrotoxicosis.

Aromatic Fluorination Enhances the Hydrophobicity and Antimicrobial Activity of Magainin 2.

ACS Appl Mater Interfaces

Suzuri Miyoshi, Koryo Obata, Hiroto Murata +4 more

Inspired by the structure of the natural antimicrobial peptide magainin 2 (MG), we developed a series of fluorinated magainin 2 analogues (FMGs) incorporating pentafluorophenylalanine residue and systematically studied their physicochemical properties and antimicrobial activities. Analytical reverse-phase high-performance liquid chromatography and circular dichroism spectroscopy demonstrated that incorporation of pentafluorophenylalanines effectively modulates the hydrophobicity and secondary structure of peptides. Membrane-disruption assays using model lipid bilayers, together with evaluations of antibacterial activity assays against Escherichia coli (E. coli) and hemolytic toxicity assays toward red blood cells, revealed that FMGs exhibit enhanced antimicrobial activity, with minimum inhibitory concentration values reduced by up to an order of magnitude relative to MG, without a substantial increase in toxicity. Notably, FMGs also retained superior antibacterial activity against a drug-resistant E. coli strain harboring the RP4 multidrug-resistance plasmid. Molecular dynamics simulations suggested that the preferential membrane-disruptive activity arises from selective binding to negatively charged bacterial membranes. These findings provide detailed structure-activity relationships for fluorinated antimicrobial peptides and highlight the introduction of fluorinated aromatic units as a powerful strategy to enhance hydrophobicity and antimicrobial activity.

A tea exosome-integrated self‑oxygenating cascade chitosan/oxidized alginate hydrogel for remodeling the hyperglycemic and hypoxic microenvironment in diabetic wound healing.

Carbohydr Polym

Li-Hua Xie, Xin-Hui Zhou, Wei-Qiu Wen +4 more

Diabetic wound healing is severely hindered by a dysregulated microenvironment characterized by hyperglycemia, persistent infection and severe hypoxia. Herein, we designed a pathology-powered therapeutic cascade hydrogel, Gel@Lip-TEx@GCu-GOX based on a dynamic polysaccharide network. This injectable and wound-adaptive carbohydrate polymer matrix not only provides a biocompatible scaffold for irregular wound coverage, but also enables the local retention and stabilization of a tea-exosome/liposome-integrated glucose oxidase catalytic system. Within the dynamic polysaccharide network, glucose oxidase (GOX) initiates hyperglycemia-to-antibacterial conversion by consuming excess glucose and producing antibacterial H2O2, thereby restricting bacterial proliferation and reducing nutrient availability. GHK-Cu further drives H2O2-to-O2 conversion, which prevents peroxide overload, alleviates oxidative injury, and improves the hypoxic wound microenvironment. In parallel, liposome-associated tea leaves-derived exosomes (TEx) protects GOX activity and provides plant exosome-guided immune reprogramming, shifting macrophages toward a reparative M2 phenotype and supporting angiogenesis. In vitro and in vivo studies confirmed that Gel@Lip-TEx@GCu-GOX exerted potent antibacterial activity, enhanced M2 polarization and angiogenesis, and markedly accelerated diabetic wound repair. This study therefore establishes a disease-microenvironment-driven catalytic hydrogel platform for transforming pathological diabetic wound signals into coordinated regenerative therapy.

KPV attenuates adipogenesis and lipid metabolism through modulation of ROS-mediated AKT/mTORC1/PPARγ signaling.

Tissue Cell

Seo-Hee An, Ji-Yeon Park, Sei-Jung Lee

Lysine-Proline-Valine (KPV), an endogenous tripeptide derived from α-melanocyte-stimulating hormone, has been recognized for its anti-inflammatory and antioxidant activities. However, its role in adipocyte differentiation has not been investigated. In this study, we investigated the regulatory effects of KPV on MDI-induced adipocyte differentiation in 3T3-L1 preadipocytes. KPV treatment dose-dependently suppressed adipocyte differentiation. Specifically, treatment with 100 μg/mL KPV reduced Oil Red O staining intensity by approximately 55% and intracellular triglyceride content by approximately 38% compared with the MDI-treated group. In addition, KPV decreased the expression of key adipogenic markers, including peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid synthase (FAS). Mechanistically, KPV attenuated reactive oxygen species (ROS) production and was associated with reduced AKT-dependent mTOR signaling and altered PPARγ phosphorylation during adipocyte differentiation. This regulatory effect was accompanied by suppression of FAS expression. In addition, in a high-fat diet-induced obesity mouse model, oral administration of KPV alleviated body weight gain, white adipose tissue expansion, liver mass increase, and obesity-associated dyslipidemia, including elevated plasma total cholesterol levels. Collectively, these findings suggest that KPV suppresses adipocyte differentiation, at least in part, in association with the modulation of ROS-related AKT/mTOR/PPARγ signaling in vitro, while its in vivo administration mitigates diet-induced obesity-related metabolic alterations. These results highlight the potential of KPV as an endogenous peptide-based candidate for the prevention and management of obesity.

Beyond GLP-1: Amylin-Based Pharmacotherapy and the Search for Better-Tolerated Weight-Loss Drugs.

Pharmacol Res

Sophia L Fischer, Tito Borner

Amylin-based pharmacotherapy has re-emerged as a promising strategy for the treatment of obesity and metabolic disease with pharmacological and neural mechanisms distinct from incretin-based therapies. Amylin is a pancreatic β-cell hormone co-secreted with insulin that contributes to postprandial glucose regulation, slows gastric emptying, suppresses glucagon secretion, and promotes satiation through actions in the central nervous system. Recent advances in peptide engineering, lipidation, and reversible albumin binding have enabled the development of long-acting amylin-based agents, including cagrilintide, eloralintide, petrelintide and NN1213. These therapies differ in their pharmacokinetic properties and receptor selectivity, ranging from more selective amylin receptor agonists to dual amylin/calcitonin receptor agonists. This distinction may be critical for understanding both efficacy and tolerability, as calcitonin receptor engagement, exposure kinetics, and downstream neural circuit recruitment may influence whether reduced food intake reflects physiological satiation or aversive signaling. In this review, we summarize the biology of amylin signaling, the historical development of amylin-based therapeutics, and the emerging clinical landscape of long-acting amylin analogs. We place particular emphasis on the tolerability profile of this drug class and discuss how receptor pharmacology, hindbrain and parabrachial circuitry, species differences, and pharmacokinetic exposure may shape nausea, malaise, and emesis. Understanding how amylin-based therapies dissociate weight-loss efficacy from gastrointestinal intolerance may guide the rational design of next-generation anti-obesity drugs with improved clinical utility.

Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice.

Nat Commun

Brittany M Hemmer, Sarah M Philippi, Ana Catarina Ferreira +3 more

There is little understanding of how aging serves as the strongest risk factor for several neurodegenerative diseases. Microglia undergo age-related maladaptive changes, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear. The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in these processes, we examined the impact of TIMP2 on microglial function. We show that TIMP2 deletion in mice exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, changes in lysosomal-associated markers and phagocytosis, and elevated levels of stress and inflammatory proteins in the brain extracellular space measured by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increases microglial CD68 and alters myelin phagocytosis. Treating aged mice with TIMP2 reverses several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced phagocytosis of physiological substrates. Our results identify TIMP2 as a modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.

Pseudo-heart failure in pregnancy complicated by preeclampsia: giant mediastinal teratoma with extrinsic cardiopulmonary compression.

BMJ Case Rep

Jose Lopez Ventosa, Josean Reyes, Alex Cedeño +1 more

A woman in her early 20s at 30 weeks of gestation presented with elevated blood pressure, transaminitis, progressive dyspnoea, orthopnoea, exertional chest pain and peripheral oedema, raising concern for preeclampsia-associated cardiopulmonary disease or peripartum cardiomyopathy. Transthoracic echocardiography showed preserved left ventricular systolic function, normal left-sided filling pressures, right ventricular dilatation and an estimated right atrial pressure of 15 mmHg; N-terminal pro-brain natriuretic peptide was 57 pg/mL. Cross-sectional imaging revealed a large multi-cystic anterior mediastinal mass occupying the left hemithorax, displacing the heart and abutting/compressing major cardiopulmonary structures. Labour was induced at 34 weeks after clinical stabilisation. Three months postpartum, the patient re-presented with worsening dyspnoea and haemoptysis and underwent complete surgical resection. Pathology confirmed mature cystic teratoma and cardiopulmonary symptoms resolved after resection.

Innate anxiety in rats determines vulnerability to social fear conditioning and social fear memory.

Psychoneuroendocrinology

Marianella Masís-Calvo, Virginie Rappeneau, Inga D Neumann

Social anxiety disorder (SAD) involves excessive fear of social situations and can be induced by social trauma. However, the underlying mechanisms of individual differences in the formation of social fear memory remain unclear. To address this gap, we adapted our mouse social fear conditioning paradigm for rats (rSFC) and compared adult male rats selectively bred for high (HAB) or low (LAB) anxiety-related behaviour and non-selected controls (NAB). HAB and LAB rats are established as a model displaying genetically determined extremes in socio-emotional behaviours. Conditioned HAB, LAB, and NAB rats all developed social fear, but with line-specific persistence. During a social fear discrimination test, HAB and LAB rats expressed social fear 24 h after acquisition, while NAB rats only showed transient social fear (up to 6 h), indicating reduced susceptibility to social trauma. Importantly, only HAB rats showed individual social fear memory, with reduced social investigation of the familiar rat encountered during social fear acquisition ("known") versus a novel ("unknown") rat. Blockade of brain V1a receptors after social fear acquisition slightly reduced generalised social fear in HAB rats and abolished their individual social fear memory, whereas central infusion of arginine vasopressin (AVP) modestly reduced generalised social fear in LAB rats. Additionally, rSFC induced a rapid corticosterone response, which was more pronounced in NAB than HAB rats. Blocking glucocorticoid synthesis before social fear acquisition slightly reduced generalised social fear in HAB rats. These findings demonstrate that innate anxiety determines the long-term formation of individual social fear memory, as assessed after a 24-h retention interval, in adult male rats and support rSFC as a useful experimental model to investigate selected neurobiological mechanisms relevant to SAD.

GnRH-receptor antagonism as a targeted approach to reproductive dysfunction in polycystic ovary syndrome.

EBioMedicine

Ludovica Cotellessa, Hélène Maitre, Frank Giton +5 more

Polycystic ovary syndrome (PCOS), recently renamed polyendocrine metabolic ovarian syndrome (PMOS), is characterised by neuroendocrine dysfunction with accelerated gonadotrophin-releasing hormone (GnRH)/luteinising hormone (LH) pulsatility driving hyperandrogenism and anovulatory infertility.

Sequential development of isolated ACTH deficiency and fulminant type 1 diabetes as delayed immune-related endocrine adverse events.

BMJ Case Rep

Mei Ishikawa, Satsuki Tanaka, Mitsuyo Shintani

A man in his 70s with lung adenocarcinoma (cStage IVA) received POSEIDON-based therapy with durvalumab, tremelimumab and chemotherapy. After six cycles, progressive disease prompted a switch to carboplatin plus nab-paclitaxel. Nineteen weeks after the final immune checkpoint inhibitor (ICI) administration, he developed fatigue and anorexia. Adrenocorticotropic hormone (ACTH) and cortisol were below assay detection limits, and a corticotropin-releasing hormone stimulation test showed no ACTH response, consistent with ICI-related isolated ACTH deficiency. Symptoms improved with hydrocortisone replacement. Five weeks later, he developed diabetic ketoacidosis, with a glucose level of 30.4 mmol/L (reference range, 3.9-6.1 mmol/L) and a ketone level of 6.3 mmol/L (<0.6 mmol/L). HbA1c and urinary C-peptide excretion were 6.9% (4.6%-6.2%) and 1.8 nmol/day (7.5-51.4 nmol/day) respectively. These findings supported a diagnosis of fulminant type 1 diabetes mellitus, considered ICI-related. This case highlights the need for continued vigilance, as immune-related adverse events may develop sequentially even after ICI therapy has ended.

Activity-dependent neuroprotective protein (ADNP) derived peptide NAP prevents musculoskeletal abnormalities in ovariectomized mice.

Front Neurosci

Liri Sophia Guz, Artur Galushkin, Illana Gozes

Estrogen is an essential hormone that critically impacts bodily and brain functions, supporting learning, memory, and motor activities. A decrease in estrogen levels is associated with cognitive decline and motor dysfunction, such as muscle weakness. While conventional hormone replacement treatments (HRT) exist, those have limitations and potentially severe side effects. NAP (davunetide) is the smallest neuroprotective peptide site of activity-dependent neuroprotective protein (ADNP), a master regulator of cognition, essential for brain formation. It is known that NAP restores ADNP activity in cases of deficiency and it has already shown potential in preventing cognitive impairment, protecting against tauopathy, and improving motor function in various animal models and in clinical trials. Based on the dynamic regulation of ADNP by the estrous cycle and its involvement in steroidogenic pathways, we hypothesize that NAP may restore ADNP activity and thus serve as an alternative to conventional hormonal treatments. To test this hypothesis, 3-month-old female ICR mice underwent bilateral ovariectomy (OVX) or sham surgery and received daily intranasal administration of NAP, estrogen, or vehicle. Results showed a significant reduction in weight-normalized forelimb grip strength in the OVX model. Interestingly, grip strength was the only test that yielded significant OVX effects, and no significant differences were observed in the novel object recognition (NOR) test or computed tomography (CT) scans. Daily intranasal administration of either NAP or estrogen resulted in an apparent increase in the weight-normalized grip strength compared to the sham-treated OVX group. Furthermore, both the NAP- and the estrogen-treated OVX mouse groups did not statistically differ from the vehicle-treated sham control. These findings suggest that NAP may effectively prevent the loss of physical force production typically seen following ovarian hormone depletion, presenting a viable, non-hormonal candidate strategy for managing musculoskeletal symptoms. We hypothesize that the lack of significance OVX effects in other parameters was due to soy-derived phytoestrogens in the current Tel Aviv University's standard diet. Thus, the standard diet may have exerted a systemic estrogenic effect that masked the expected physiological phenotypes typically observed in OVX models. Future replication using phytoestrogen-deficient food is required to isolate the specific neuroprotective and musculoskeletal effects of NAP from dietary influence and clarify broader therapeutic benefits.

Effectiveness and Safety of Combined Semaglutide and Dapagliflozin Therapy in Type 2 Diabetes: A Retrospective Cohort Study.

Cureus

Mahmoud Alzahrani, Najlaa Alsudairy, Zahra Al Asmari +6 more

Combination therapy with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors may provide complementary metabolic, cardiovascular, and renal benefits in type 2 diabetes mellitus (T2DM). However, real-world evidence from Middle Eastern populations remains limited. This study evaluated the effectiveness and safety of combined semaglutide and dapagliflozin therapy in routine clinical practice.

Reframing GLP-1 Therapies as Cardiometabolic Health Drugs: Beyond the Race to Weight Loss.

J Am Coll Cardiol

Harlan M Krumholz

Burden and Risk of Depression in Patients Receiving Semaglutide: A Systematic Review and Meta-Analysis.

Clin Obes

Gaurab Bhaduri, Shilanjan Roy, Anchin Kalia +2 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, are widely used for Type 2 diabetes mellitus (T2DM), obesity and related metabolic conditions. Evidence on potential neuropsychiatric effects remains inconsistent. This systematic review and meta-analysis evaluated depression risk among patients receiving semaglutide. Following PRISMA 2020 guidelines, major biomedical databases, trial registries, pharmacovigilance databases, conference abstracts and grey literature were searched from inception to January 2026. Eligible studies included randomised controlled trials, observational studies, large database analyses and pharmacovigilance disproportionality studies involving patients receiving semaglutide. Risk of bias was assessed using ROBINS-I and the Newcastle-Ottawa Scale. The pooled risk ratio for depression was 1.25 (95% CI: 0.95-1.65; I2 = 98%). For anxiety and suicidal ideation/attempt, pooled risk ratios were 1.22 (95% CI: 0.93-1.60; I2 = 99%) and 1.20 (95% CI: 0.90-1.62; I2 = 92%), respectively. No statistically significant differences were observed between semaglutide and comparator/placebo groups for outcomes. Pooled estimates did not show a statistically significant increase in depression, anxiety or suicidal ideation/attempt among patients receiving semaglutide compared with comparator groups. However, the certainty of evidence was limited by substantial heterogeneity, risk of bias and reliance on heterogeneous data sources, including spontaneous-reporting studies. These findings are reassuring but should be interpreted as the absence of a detected increased risk in the available evidence, rather than definitive proof of no psychiatric risk.

Real-world semaglutide in obesity cohort: effectiveness, safety and persistence across sex, BMI, and prior GLP-1RA treatment.

Front Endocrinol (Lausanne)

Ilaria Milani, Maria Eugenia Parrotta, Marianna Chinucci +6 more

Semaglutide has shown significant efficacy in several clinical trials for the treatment of obesity. However, real-world data on early weight loss and metabolic response in obesity without diabetes cohort are still limited, particularly with respect to individual patient factors. This study aims to evaluate the real-world effectiveness of semaglutide on anthropometric and metabolic parameters in an obesity cohort, including weight loss (kg and percent) and the percentage of participants achieving the 5%, 10% and 15% weight loss targets at mean 3-month, 6-month and 12-month follow-up. In addition, an assessment of safety and reasons for discontinuation, and sub-analyses of anthropometric outcomes by prior liraglutide exposure, sex, and BMI categories will be included.

Association of Glucagon-Like Peptide-1 Receptor Analogues and Laryngeal Symptoms in Obese Adults.

Laryngoscope

Priyanka Shah, David Kayekjian, Shaun A Nguyen +2 more

Given the unprecedented rise in glucagon-like peptide-1 receptor analogue (GLP-1RA) therapy over the past decade, we aimed to investigate potential unintended laryngeal manifestations.

PT320, a GLP-1 receptor agonist, mitigates nucleus accumbens-associated depression- and anxiety-like behaviors in MitoPark mice of Parkinson's disease.

J Parkinsons Dis

Kuan-Yin Tseng, Tung-Tai Kuo, Pi-Kai Chang +7 more

BackgroundNeuropsychiatric symptoms such as anxiety and depression substantially impair quality of life in Parkinson's disease (PD), yet the underlying neural circuits remain poorly defined. The MitoPark (MP) mouse, a dopaminergic mitochondrial dysfunction model, recapitulates both motor and non-motor features of PD.ObjectiveTo determine whether the sustained-release GLP-1 receptor agonist PT320 (exenatide) alleviates anxiety- and depression-like behaviors in MP mice and to identify the involved neural substrates.MethodsThe temporal progression of anxiety- and depression-like behaviors was characterized in MP mice. PT320 was administered biweekly starting at either 5 weeks (early treatment) or 15 weeks (late treatment), with longitudinal evaluation until 20 weeks. Behavioral outcomes were correlated with molecular, transcriptomic, and neurochemical analyses in the nucleus accumbens (NAc), including Western blotting, bulk RNA sequencing, fast-scan cyclic voltammetry, and tyrosine hydroxylase immunostaining.ResultsEarly PT320 treatment effectively prevented the emergence of anxiety- and depression-like phenotypes in MP mice. Behavioral improvement was associated with restoration of BDNF signaling and activation of the Akt-CREB pathway in the NAc. Transcriptomic analysis revealed increased expression of Akt3, CREB, BDNF, and TrkB, along with modulation of genes related to mitochondrial homeostasis. Late PT320 treatment partially ameliorated neuropsychiatric deficits, coinciding with enhanced phasic dopamine release and recovery of tyrosine hydroxylase expression in the NAc.ConclusionsThese findings identify the NAc as a critical regulator of affective disturbances in this PD model. By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression.

Covalent Anchoring of Enzyme-Activatable Fluorescent Signals for in Situ Imaging and Longitudinal Staging of Cellular Senescence in Pulmonary Fibrosis.

Small

Feiyi Chu, Bin Feng, Huanfeng Tian +8 more

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease caused by the pathological accumulation of senescent cells. In this fibrotic microenvironment, senescence-associated β-galactosidase (SA-β-Gal) serves as a key biomarker. However, existing SA-β-Gal molecular probes suffer from signal diffusion and rapid clearance due to the extracellular leakage, compromising imaging fidelity. To address this issue, an enzyme-activated covalent labelling strategy is proposed, and as a design paradigm developing TCFM-Gal, a imaging tool integrating β-galactosidic fluorophore with an ortho-difluoromethyl leaving group. Upon SA-β-Gal-mediated hydrolysis, TCFM-Gal generates a quinone methide intermediate that covalently anchors to surrounding nucleophiles, confining fluorescence within lysosomes. In senescent cells, TCFM-Gal achieves extended lysosome-retained imaging, maintaining over 85% signal retention within 24 h. In the IPF model, TCFM-Gal enables longitudinal tracking of senescent cells and maintains a high signal intensity after 24 h. Rapid circulatory washout and high interstitial fluid pressure make conventional probes ineffective in the lungs. TCFM-Gal overcomes this not just by sensing, but by anchoring the signals in situ. Moreover, TCFM-Gal facilitates staging assessments of fibrosis progression by quantifying the senescence burden across disease phases. This study establishes an enzyme-activated covalent labeling paradigm for high-fidelity senescence imaging, advancing the spatiotemporal mapping of senescence in lung diseases.

Intestinal pooling of taurine conjugated bile acids is associated with tissue aging and senescent immune evasion.

Front Immunol

Jinzhuo Tan, Wenyan Xiong, Yingna Feng +3 more

Aging drives metabolic decline and the accumulation of senescent cells that evade immune clearance. The mechanisms linking host-microbiome co-metabolism to peripheral tissue deterioration remain unclear. We hypothesized that age-dysregulated enterohepatic bile acid (BA) signaling directly promotes systemic aging and immune senescence.

Mediterranean diet impact on plasma proteins: biomarker networks linking nutrition to the modulation of inflammation and oxidative stress.

Front Nutr

Fátima Cardoso, Eduardo Costa-Camilo, Isabel Duarte +4 more

The Mediterranean diet (MedDiet) is widely recognized for its role in preventing chronic and age-related diseases, largely attributed to its richness in plant-based foods and bioactive compounds. To explore the underlying molecular mechanisms, two systematic literature searches were conducted using PubMed and Web of Science. The first assessed the evidence on the health effects of key MedDiet components and the second focused on plasma biomarkers of inflammation and oxidative stress. Protein-protein interaction network analysis revealed a tightly connected metabolic network integrating inflammatory mediators and metabolic regulators. Central nodes included key inflammatory markers such as interleukin-6, tumor necrosis factor and C-reactive protein (CRP), alongside proteins involved in lipid metabolism and metabolic homeostasis. Enrichment analysis highlighted pathways related to acute inflammatory response, lipid localization and storage and plasma lipoprotein particle clearance, supporting a role in regulation of immune and metabolic processes. An additional network integrating cardiovascular aging biomarkers suggested a partial separation between systemic inflammatory pathways and markers of myocardial stress and injury, with CRP emerging as a potential link between these processes. Overall, these findings indicate that the MedDiet may exert its health benefits through systems-level modulation of interconnected metabolic pathways, contributing to the regulation of inflammation, lipid metabolism and cardiovascular function.