Search Results (3,150)

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular–kidney–metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit. Full article

Ischemia with non-obstructive coronary arteries (INOCA) and coronary microvascular dysfunction (CMD) are increasingly recognized causes of angina, reduced quality of life, and elevated cardiovascular risk, yet mechanistic heterogeneity complicates diagnosis and treatment. This narrative review synthesizes evidence from clinical guidelines, consensus documents, landmark trials, cohorts, mechanistic studies, and high-quality reviews identified through structured, non-exhaustive searches of PubMed/MEDLINE, Google Scholar, and major cardiovascular society documents. Current evidence indicates that endothelial mitochondria function primarily as signaling organelles, regulating reactive oxygen species, nitric oxide bioavailability, endothelium-dependent hyperpolarization, calcium signaling, inflammatory activation, mitophagy, and endothelial survival. Cardiometabolic risk factors, aging, chronic kidney disease, and postmenopausal hormonal changes may converge on mitochondrial quality-control and redox pathways, contributing to CMD susceptibility and sex-specific vulnerability. However, direct human evidence linking endothelial mitochondrial dysfunction causally to CMD defined by invasive coronary function testing remains limited. Coronary physiological testing and acetylcholine provocation are validated tools for CMD endotyping, whereas mitochondrial biomarkers remain investigational. Endotype-guided diagnosis and management remain central, while mitochondria-targeted strategies require prospective CMD-specific validation. Full article

Background/Objectives: Dietary patterns characterized by excess saturated fat intake contribute to obesity, type 2 diabetes, and cardiac metabolic dysfunction. Ceramides, bioactive sphingolipids synthesized in response to nutrient overload, have emerged as key molecular mediators linking dietary lipid composition to alterations in cardiac metabolic signaling. This review aims to integrate current evidence on diet-induced ceramide remodeling and its impact on intracellular pathways regulating cardiac metabolism. Methods: We analyzed experimental and clinical studies investigating the effects of high-fat and Western-type diets on myocardial ceramide synthesis, lipidomic remodeling, and downstream signaling pathways. Evidence from animal models, genetic and pharmacological interventions, nutritional studies, and circulating biomarker analyses was examined to delineate mechanistic and translational insights. Results: Saturated fatty acid excess, particularly palmitate, activates the de novo ceramide synthesis pathway in the myocardium, promoting accumulation of specific ceramide species. This remodeling impairs insulin signaling through Akt inhibition, protein phosphatase 2A activation, and PKCζ-dependent mechanisms, contributing to cardiac metabolic inflexibility. Ceramides further disrupt mitochondrial function by altering electron transport chain activity, increasing reactive oxygen species production, and modulating mitophagy and apoptotic signaling. Lipidomic studies highlight species-specific effects, with C16-ceramides frequently associated with adverse metabolic and cardiovascular outcomes, whereas very-long-chain ceramides may exert distinct functional roles. Circulating ceramide profiles have also been linked to diet-associated cardiovascular risk. Conclusions: Diet-induced ceramide remodeling represents a central molecular axis connecting dietary lipid excess to altered cardiac metabolic signaling. Targeting sphingolipid metabolism through nutritional or pharmacological strategies may offer novel opportunities for preventing and managing diet-associated cardiac dysfunction. Full article

Background: Obesity has evolved from a morphometric descriptor to a chronic, relapsing, multisystem disease in which low-grade adipose-tissue inflammation, insulin resistance, endothelial dysfunction, and a prothrombotic, pro-tumorigenic milieu coexist. Venous thromboembolism (VTE) and malignancy share this substrate through a well-established bidirectional link: within twelve months of an unprovoked deep vein thrombosis (DVT), 6–15% of patients are diagnosed with occult cancer, a substantial proportion of which are already locally advanced or metastatic at detection. In this context, obesity acts as a dual amplifier of both thrombotic and oncologic risk, making the post-DVT patient with an incidentally diagnosed cancer a paradigmatic candidate for integrated management. Objective: To propose an evidence-based, unifying cardiometabolic and antithrombotic clinical framework that reconciles (i) risk-stratified screening for occult malignancy after unprovoked DVT, (ii) contemporary pharmacotherapy of obesity, and (iii) cancer-associated thrombosis (CAT) management, in the light of evidence published through 2025. Methods: Narrative synthesis based on a structured literature search (PubMed/MEDLINE, Embase, Scopus; 2000–March 2025) of current guidelines (ISTH, ASH, ESC Cardio-Oncology, EASO) and pivotal randomized evidence on GLP-1 and dual GLP-1/GIP receptor agonists (semaglutide, tirzepatide), SGLT2 inhibitors (empagliflozin, dapagliflozin), and direct oral anticoagulants (DOACs), with critical interpretation of recent meta-analytic data on oncologic signals, cardiovascular outcomes, and bleeding safety. Results: Three evidence-based pillars emerge: (1) limited screening complemented by age- and sex-specific testing in patients ≥ 50 years with unprovoked DVT, enhanced by FDG-PET/CT for high-risk phenotypes in which obesity itself degrades the sensitivity of clinical examination and conventional imaging; (2) GLP-1/GIP receptor agonist-based anti-obesity pharmacotherapy, associated in observational cohorts with a 17% relative reduction in overall cancer incidence (HR 0.83; 95% CI 0.76–0.91) and neutral-to-reassuring oncologic signals, but requiring cautious, case-by-case use in patients with active cancer because of the risk of accelerating sarcopenia and cachexia; and (3) apixaban as the preferred DOAC for cancer-associated thrombosis, with a superior efficacy-to-bleeding ratio in network meta-analyses and a reduced-dose extended strategy now validated by the API-CAT trial. Conclusions: Patients with obesity presenting with unprovoked DVT and an incidentally detected cancer embody a cardiometabolic–antithrombotic continuum. A framework integrating structured occult-cancer screening, judicious obesity pharmacotherapy, and apixaban-preferred anticoagulation—coordinated by a multidisciplinary team and illustrated here by a case-based pathway—offers the most rational, evidence-aligned approach. Prospective, dedicated trials in this specific phenotype are urgently warranted. Full article

The Warburg effect is better understood as regulated metabolic plasticity rather than mitochondrial failure. Many malignant cells retain functional mitochondria while increasing aerobic glycolysis, lactate production, and redox remodeling to support growth, immune escape, and adaptation to microenvironmental stress. Within the context of the cancer microenvironment, this review examines xylitol as a hypothetical metabolic modifier within a broader host-microbe-mitochondria framework. Xylitol, a five-carbon sugar alcohol, is derived endogenously through the pentose phosphate pathway (PPP) and the glucuronate–xylulose pathway, and is metabolized efficiently in humans, rats, and pigs through xylitol dehydrogenase (XDH) in hepatic mitochondria and the cytosol; whereas, it is less tolerated by obligate carnivores who lack this enzyme. Preclinical studies show that partial substitution of glucose with xylitol can reduce proliferation and glycolytic markers in oral squamous carcinoma models, and preliminary studies link xylitol to glutathione depletion, endoplasmic reticulum (ER) stress, autophagy-associated death, and altered tumor metabolomics. On the other hand, oral pathogens such as Fusobacterium nucleatum and Porphyromonas gingivalis promote tumor stemness, extracellular vesicle signaling, metastasis, and immune evasion. In addition, Streptococcus mutans, the primary cariogenic pathogen, contributes to systemic bacteremia and epithelial–mesenchymal transition. Oral and gut microbiomes modulate macrophage polarization, T cell activity, and the senescence-associated secretory phenotype (SASP), possibly promoting cancer immune evasion. The anti-adhesive properties of xylitol may limit pathogen attachment to immune cell receptors, reducing the generation of pro-tumorigenic senescent immune cells. Xylitol also offers metabolic benefits, a low glycemic index, partial insulin-independent metabolism, and potential diabetes-prevention activity that are relevant, considering the established link between metabolic disease and cancer risk. A recent study reported that higher levels of endogenous xylitol were associated with adverse cardiovascular events, but confirmation of this requires large scale prospective studies. The evolutionary dietary context of MIS 6, during which hominin populations in sub-Saharan Africa depended on polyol-rich underground storage organs, provides a biological basis for human tolerance of xylitol. As a result, we hypothesize that xylitol may be a context-dependent metabolic modifier within an integrated host–microbe–mitochondria–cancer stem cell network. Full article

Atherosclerosis is a chronic inflammatory disease characterized by progressive vascular dysfunction and remains a leading cause of cardiovascular morbidity and mortality worldwide. Endothelial dysfunction is an early and critical event in atherogenesis, contributing to inflammation, leukocyte recruitment, plaque progression, and thrombotic complications. Increasing evidence indicates that vascular endothelial cells use bioelectrical signaling mechanisms to integrate mechanical, metabolic, and inflammatory cues and maintain vascular homeostasis. At the core of these regulatory networks are ion channels and transporters, which coordinate membrane potential, ionic fluxes, calcium homeostasis, redox balance, and downstream biochemical signaling to regulate endothelial function in vascular health and disease. Dysregulation of these pathways may promote oxidative stress, inflammation, endothelial senescence, apoptosis, endothelial-to-mesenchymal transition, and impaired vasodilatory function, thereby contributing to atherosclerotic progression. Understanding how ion channels regulate endothelial function may provide important insights into atherosclerosis and facilitate the development of novel therapeutic strategies aimed at restoring endothelial homeostasis and reducing cardiovascular risk. Full article

Skeletal muscle is increasingly recognized as a dynamic secretory organ capable of translating contractile, metabolic, mechanical and inflammatory stimuli into systemic biological signals. Among these signals, myokines and myokine-associated exerkines mediate communication between skeletal muscle and distant organs, influencing glucose and lipid metabolism, immune regulation, bone remodeling, neuroplasticity, vascular function and tissue regeneration. Representative mediators considered include IL-6, IL-15, myostatin, follistatin, decorin, FNDC5/irisin, FGF21, myonectin/CTRP15, BDNF, cathepsin B, SPARC, apelin and extracellular-vesicle cargo. However, current evidence remains fragmented across individual molecules, exercise modalities, sampling windows, assay platforms and disease contexts. This narrative mechanistic review proposes the concept of the “myokine adaptome” as an integrated, context-dependent signaling network through which skeletal muscle contributes to systemic homeostasis in health and disease. We synthesize evidence on cellular triggers of myokine release, including AMPK-PGC-1α signaling, mTORC1-dependent mechanical sensing, calcium flux, redox signaling, inflammatory pathways and extracellular-vesicle-mediated communication. We further examine how exercise modality, aging, obesity, type 2 diabetes, sarcopenia, osteoporosis, cardiovascular disease, COPD, cancer/cachexia and chronic inflammation reshape myokine production and target-organ responsiveness. The central argument is that myokine biology should be interpreted not as a catalog of isolated mediators, but as a dynamic adaptive code defined by signal amplitude, temporal pattern, molecular composition, delivery route and recipient-tissue sensitivity. Its novelty is operational rather than nominal: it requires source confidence, temporal kinetics, co-signal context, delivery route and functional decoding to be evaluated together. This framework may improve biomarker design, disease-specific exercise prescription and therapeutic strategies aimed at restoring adaptive muscle–organ communication. The framework is further strengthened by testable predictions concerning adaptive pulsatility, modality-specific signatures, source attribution, recovery quality, disease-specific decoding and the superiority of multi-marker panels over single-molecule readouts. Full article

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, have revolutionized the management of type 2 diabetes and obesity. Recent evidence suggests these agents may influence athletic performance through effects on body composition, energy metabolism, and cardiovascular function. This narrative review critically evaluates whether incretin therapies could constitute doping under World Anti-Doping Agency (WADA) criteria. We narratively reviewed the literature on incretin pharmacology, metabolic effects relevant to athletic performance, and anti-doping regulations, searching PubMed, Scopus, and Web of Science using terms including “GLP-1 receptor agonists”, “DPP-4 inhibitors”, “doping”, “athletic performance”, “WADA”, and “sports pharmacology”, without date restrictions. GLP-1 RAs (semaglutide, liraglutide, tirzepatide, exenatide) induce substantial weight loss (predominantly fat mass) but also reduce lean mass by 20–30% of total weight loss. Preclinical studies demonstrate enhanced exercise endurance, mitochondrial biogenesis, and glucose uptake via GLP-1R/AMPK signaling. However, clinical trials show no consistent improvement in physical performance in humans. Currently, incretin therapies are not listed on the WADA Prohibited List. While incretin therapies offer theoretical performance-enhancing potential through weight management and metabolic optimization, current evidence does not support classification as doping agents. Continued surveillance is warranted as misuse patterns emerge. Full article

Background: Cardiometabolic syndrome is a cardiovascular disease characterized by metabolic dysregulation, with obesity triggering overactivation of the cardiac Renin–Angiotensin System (RAS). This leads to pathological cardiac changes and dysfunction. Empagliflozin (EMPA) modulates local RAS components in the kidney and liver, but its role in regulating cardiac RAS needs further study. Methods: Twenty-four male Wistar rats were separated into the following two groups: (1) control and (2) metabolic syndrome (MS) fed a high-fat diet, and after 8 weeks, half of each group was treated with EMPA (10 mg/kg) for 8 subsequent weeks. Finally, the animals underwent echocardiography, and under sodium thiopental anesthesia, blood samples were taken for FBS and lipid profile measurement. Finally, the left ventricle was isolated and used to measure the levels of proteins in the RAS pathway, including AngII (Angiotensin2), AT1R (Angiotensin2type1receptor), AT2R (Angiotensin2type2 receptor), and downstream pathway proteins pERK1/2 (Phosphorylated Extracellular Signal-Regulated Kinase1/2), NHE1 (Na+/H+ Exchanger1), NCX (Na+/Ca²+Exchanger), and NLRP3 (NOD-like-receptor-protein3) by Western blot, as well as ROS (reactive oxygen species) levels by ELISA. Results: EMPA treatment in MS significantly decreased FBS, TG, and LDL, increased HDL, and improved cardiac function. It was also associated with increased AT2R expression and attenuation of AngII, AT1R, pERK1/2–NHE1–NCX signaling, oxidative stress, and inflammatory markers (ROS and NLRP3) in rats with MS. Conclusion: Our findings suggest that EMPA treatment is associated with improvement in selected local cardiac RAS components and modulation of the pERK1/2–NHE1–NCX signaling pathway, along with reduced oxidative stress, decreased inflammation, and improved cardiac function in MS. Full article

Background and Objectives: Rheumatic diseases confer excess cardiovascular risk, yet prognosis after acute coronary syndrome (ACS) in contemporary angiography-treated care remains incompletely characterized, particularly when psychiatric multimorbidity is considered. We evaluated whether documented rheumatic disease was associated with psychiatric comorbidity and post-discharge mortality after ACS. Materials and Methods: We retrospectively analyzed a predefined two-center registry extract of 2950 consecutive patients who underwent coronary angiography for ACS. Documented rheumatic disease was identified from diagnoses recorded in admission history, prior medical records, or discharge documentation and was not re-adjudicated. The primary outcome was post-discharge all-cause mortality. Results: Documented rheumatic disease was present in 106 patients (3.6%). Compared with patients without documented rheumatic disease, exposed patients were older, more often women, more often hypertensive, and more likely to have a documented psychiatric disorder (25.5% vs. 14.1%). Short-term mortality was similar, whereas crude overall long-term mortality was higher (27.4% vs. 19.3%). Among hospital survivors with usable follow-up, post-discharge survival was worse (log-rank p = 0.013). Documented rheumatic disease was associated with higher post-discharge mortality in unadjusted analysis (hazard ratio 1.66, 95% confidence interval 1.11–2.48) and in a prespecified parsimonious model (adjusted hazard ratio 1.56, 95% confidence interval 1.04–2.34); the association attenuated and was no longer statistically significant in a broader exploratory model (adjusted hazard ratio 1.35, 95% confidence interval 0.87–2.07). Documented psychiatric disorder independently predicted mortality. Conclusions: In angiography-treated ACS, documented rheumatic disease was associated with greater psychiatric comorbidity and worse post-discharge survival in a small, documentation-defined, heterogeneous subgroup. Because the signal attenuated in broader exploratory adjustment and exposure ascertainment was documentation-based, the findings should be regarded as hypothesis-generating rather than disease-specific or causal. Full article

Background/Objectives: Psilocibin (PSY), a serotonergic hallucinogen, has attracted increasing scientific interest due to its therapeutic potential, particularly in treatment-resistant depression. In parallel with its growing clinical and research relevance, important questions have emerged regarding its safety profile, including potential effects on the liver, kidneys, cardiovascular system, and immune function. The aim of this narrative review was to systematically collect, critically appraise, and organize the dispersed evidence regarding potential multi-organ safety signals associated with PSY exposure. Methods: A narrative review was conducted including preclinical studies, pharmacological investigations, available clinical data, and published case reports, including reports of mushroom-related intoxications involving PSY-containing species. All available sources addressing potential toxicological outcomes associated with PSY were considered, regardless of exposure context, in order to reflect the current state of evidence. Results: The available evidence base is limited and heterogeneous, consisting primarily of case reports, observational data, and mechanistic preclinical studies. Reported adverse events are rare and frequently confounded by polysubstance use, uncertainty of dose, co-ingestion of other compounds, and lack of exposure standardization. Despite these limitations, biologically plausible mechanisms related to serotonergic receptor activation provide a rationale for further investigation of potential organ-specific effects. However, current controlled clinical data do not provide consistent evidence supporting intrinsic multi-organ toxicity of PSY. Conclusions: Current evidence does not confirm clinically meaningful intrinsic multi-organ toxicity of PSY under controlled conditions. Nevertheless, the available literature suggests the presence of potential safety signals that warrant further systematic evaluation. In the context of growing clinical interest in PSY, this review provides a structured synthesis of current knowledge and highlights critical gaps in understanding its organ-specific safety profile. Full article

Background and Objective: Romosozumab carries a warning for potential severe cardiovascular events, while denosumab is widely used for osteoporosis but requires safety considerations in advanced chronic kidney disease (CKD). Given the limited direct real-world evidence comparing these treatments, in this study, we aimed to compare the cardiovascular and survival outcomes associated with romosozumab versus denosumab in adults with CKD. Materials and Methods: In this retrospective propensity score-matched cohort study, we utilized de-identified electronic health records from the TriNetX Global Collaborative Network, where eligible participants were adults aged 40 to 90 years with CKD who initiated either romosozumab or denosumab. Patients with bone/bone marrow malignancies or recent acute cardiovascular events were excluded. Following 1:1 propensity score matching based on demographics, diagnoses, medications, and laboratory characteristics, patients were followed for up to 1095 days. The primary outcome was a composite cardiovascular measure (all-cause mortality, acute myocardial infarction, or cerebrovascular event), while secondary outcomes included the individual components of the composite outcome and acute heart failure. Outcomes were evaluated using fixed-window cumulative risks, risk ratios (RRs), odds ratios, and hazard-ratio estimates. Results: After 1:1 propensity score matching, 1201 patients remained in each cohort; the mean age was 74.1 years in the romosozumab cohort and 74.2 years in the denosumab cohort, and 94.9% and 93.8%, respectively, were women. Romosozumab was associated with lower 1095-day cumulative risk of the composite cardiovascular outcome than denosumab (12.6% vs. 18.8%; RR, 0.668 [95% CI, 0.553–0.808]), as well as lower cumulative risk of cerebrovascular event (5.0% vs. 7.0%; RR, 0.714 [95% CI, 0.518–0.985]), all-cause mortality (6.6% vs. 9.5%; RR, 0.693 [95% CI, 0.526–0.913]), acute myocardial infarction (3.8% vs. 6.2%; RR, 0.613 [95% CI, 0.429–0.878]), and heart failure (2.7% vs. 6.1%; RR, 0.438 [95% CI, 0.292–0.659]). Conclusions: In this propensity score-matched EHR cohort of adults with CKD, cardiovascular and survival estimates associated with romosozumab versus denosumab varied by follow-up window and analytic approach. Although 1095-day fixed-window cumulative risks were lower in the romosozumab cohort, corresponding time-to-event estimates were neutral or directionally inconsistent. These findings should not be interpreted as evidence of cardioprotection or causal superiority but rather as showing no clear and consistent excess cardiovascular risk signal for romosozumab compared with denosumab. Full article

Hypogonadism is increasingly recognized as an independent cardiovascular risk factor, with testosterone deficiency associated with endothelial dysfunction, increased thrombotic risk, and adverse cardiovascular outcomes. Circulating biomarkers provide valuable insights into the vascular health status of hypogonadal men and the cardiovascular effects of testosterone replacement therapy (TRT). This comprehensive review examines the molecular basis of testosterone action on the cardiovascular system and synthesizes evidence on circulating cardiovascular biomarkers in hypogonadism, including endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), platelet markers, endothelial activators, adhesion molecules, and inflammatory/oxidative stress markers. We also compare the cardiovascular safety profiles of transdermal versus intramuscular testosterone formulations. Hypogonadal men exhibit reduced circulating EPCs, elevated EMPs, increased platelet reactivity, higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA), and increased inflammatory markers (hsCRP, IL-6, TNF-α). TRT improves most of these biomarkers through androgen receptor (AR)-dependent and AR-independent mechanisms involving PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4 axis modulation, and NF-κB pathway suppression. Current evidence suggests that transdermal testosterone formulations may offer advantages regarding hematological safety and more stable testosterone exposure; however, definitive evidence demonstrating superior cardiovascular outcomes compared with intramuscular formulations remains limited. Circulating cardiovascular biomarkers are significantly altered in hypogonadism and improve with TRT. Available data suggest that transdermal testosterone formulations may offer a more favorable cardiovascular safety profile than intramuscular preparations, particularly with respect to erythrocytosis and pharmacokinetic stability, although head-to-head randomized trials with hard cardiovascular endpoints are still needed. Understanding the molecular mechanisms underlying these changes is essential for optimizing TRT in hypogonadal men with cardiovascular risk factors. The cardiovascular safety advantage of transdermal formulations is currently supported primarily by pharmacokinetic and hematological evidence; direct comparative evidence from randomized trials with hard cardiovascular endpoints remains unavailable. Full article

In this study, an exploratory transcriptomic investigation was conducted to evaluate the feasibility of using feather transcriptomics to detect sex differences and gene responses to physiological changes in chickens. Feathers represent a promising non-invasive biological source of RNA, as the feather pulp of growing feathers contains living cells capable of active transcription. Growing feathers were collected from 150-day-old male and female chickens (Bionda Piemontese, a slow-growing breed) raised under a free-range system and fed two finisher diets differing in lipid content: low-lipid (LL, ether extract 3.6%) and high-lipid (HL, ether extract 9.3%) diets. RNA was extracted from feather pulp, and 12 pools were subjected to whole RNA-Seq analysis. The study was designed as 2 × 2 factorial experiments investigating the effects of diet and sex on gene expression. A total of 17,360 transcripts were detected and used for downstream analyses. Differential gene expression and functional enrichment analyses were performed. The main effects of diet and sex were estimated with an additive design using the DEseq2 package, while for the sex-specific diet analyses, subgroup comparisons were conducted on the RaNA-Seq platform. The analysis of the main effect of diet reveals that three genes associated with ether lipid metabolism (PLA2G10, PLA2G4F, and ENPP6) were upregulated in chickens fed the HL diet. In roosters, HL feeding significantly altered the expression of APOA1 and SLC27A4, suggesting an effect on lipid transport and metabolic regulation within the PPAR signaling pathway. In contrast, hens showed differential expression primarily in pathways related to apelin signaling, extracellular matrix remodeling, and cardiovascular function, rather than classical lipid metabolism pathways; additionally, gene set enrichment analysis indicated a limited enrichment of linoleic acid metabolism, suggesting secondary involvement of lipid metabolic processes. These findings are consistent with those in the literature reporting sex-related differences between males and females. The results further suggest that transcriptomic responses to dietary lipid supplementation can be investigated through the expression of selected candidate genes in feather pulp. Among the genes identified, PLA2G10, PLA2G4F, ENPP6, APOA1, and SLC27A4 emerged as potential molecular markers associated with dietary treatment, and the importance of sex-dependent transcriptional responses was highlighted. In conclusion, this study demonstrates the potential of feather pulp as a viable source of RNA for transcriptomic analyses in live chickens, providing a minimally invasive alternative to conventional tissue sampling. These preliminary results also support the hypothesis that feathers represent a practical and ethically favorable tissue for future nutrigenomic and genetic improvement studies, ultimately supporting more sustainable poultry production. Full article

Testicular receptor 4 (TR4, NR2C2) is an orphan nuclear receptor involved in the regulation of metabolism, inflammation, cardiovascular disease, and cancer. Accumulating evidence indicates that TR4 exhibits functional plasticity, exerting protective or pathogenic effects depending on tissue and disease context, and sometimes displaying opposing roles within the same disease. However, the mechanisms underlying this functional duality remain poorly understood. Recent studies indicate that TR4 activity is determined not only by the receptor itself but also by dynamic coregulatory networks. Through interactions with coactivators, corepressors, epigenetic regulators, and environmental signaling pathways, TR4 integrates metabolic cues to generate context-dependent transcriptional programs. Coactivator networks centered on PGC-1α, steroid receptor coactivator (SRC) family members, and CBP/p300 support oxidative metabolism and anti-inflammatory responses, whereas RIP140-, NCoR/SMRT-, and HDAC-associated networks promote lipid accumulation, chronic inflammation, fibrosis, and tumor progression. Regulators such as JAZF1 further influence TR4 activity by reshaping coregulator recruitment and target-gene selection. In this review, we summarize the structural basis of TR4 regulation and discuss how coregulatory network remodeling governs its functions in metabolic, cardiovascular, inflammatory, and malignant diseases. We propose that TR4 functions as a context-dependent transcriptional platform whose activities are defined by its coregulatory landscape, providing a framework for precision therapies. Full article