Search Results (81)

Metabolic diseases are characterized by a complex interplay between metabolic dysregulation and chronic low-grade inflammation. Fetuin-A (FetA), a liver-derived hepatokine, has emerged as a key mediator linking these processes through its pro-inflammatory and insulin resistance-promoting effects. Accumulating evidence indicates that FetA not only serves as a biomarker but also actively contributes to disease pathogenesis by modulating multiple signaling pathways. In this review, we present an overview of the molecular mechanisms underlying FetA-induced suppression of peroxisome proliferator-activated receptor (PPAR) signaling, a central regulator of metabolic homeostasis. Emerging evidence suggests that FetA may promote Toll-like receptor 4 (TLR4)-mediated inflammation, activate nuclear factor kappa B (NF-κB) signaling, suppress key energy regulators such as Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), and inhibit PPAR activity through Wnt and extracellular signal-regulated kinase (ERK) pathways. These interconnected mechanisms may contribute to impaired lipid metabolism, increased insulin resistance, and metabolic inflammation. Furthermore, we highlight the role of FetA glycosylation, particularly fucosylation, as a regulatory layer influencing its biological activity. Fucosylated FetA may more effectively activate TLR4 signaling and suppress PPAR activity, suggesting functional heterogeneity among glycoforms. Overall, the FetA–PPAR interaction may represent a key mechanistic link between metabolic inflammation and disease progression. Full article

Polycystic ovary syndrome (PCOS) is frequently accompanied by visceral obesity, insulin resistance, low-grade chronic inflammation, and metabolic syndrome (MetS). These alterations promote significant dysfunction in adipose tissue and liver metabolism through cytokine production. Growing evidence indicates that the interaction between hepatokines and adipokines plays a central role in the development of metabolic and hepatic abnormalities in women with PCOS. This narrative review was conducted to analyze the relationship between adipose tissue dysfunction and liver metabolic impairment in women with PCOS, emphasizing the involvement of hepatokines and adipokines in insulin resistance, inflammation, hepatic steatosis, hepatic fibrosis and MetS. From this perspective, contemporary clinical, biochemical, and molecular studies were reviewed to evaluate how adipocyte-derived factors and hepatocyte-derived cytokines influence metabolic homeostasis in the liver and adipose tissue in women with PCOS. Increased visceral adiposity in PCOS enhances the release of free fatty acids (FFAs) to the liver, resulting in hepatotoxicity, oxidative stress, and hepatic inflammation. Several hepatokines, including fetuin-A, angiopoietin-like protein 3 (ANGPTL3), selenoprotein P(Sep-P), and hepassocin (HPS), show abnormal circulating levels in PCOS and are strongly associated with insulin resistance, dyslipidemia, and progression to hepatic steatosis. In contrast, fibroblast growth factor 21 (FGF-21), follistatin, and interleukin (IL-6) may exert dual effects. Adipokines, such as resistin, visfatin, apelin, and retinol-binding protein 4 (RBP-4), contribute to chronic inflammation, impaired glucose metabolism, androgen excess, and hepatic steatosis and fibrosis. Some of these adipokines, such as leptin and vaspin, may exert both beneficial and detrimental effects, while others, including chemerin and omentin, appear to play predominantly beneficial roles in metabolism. Reduced adiponectin-to-leptin levels further aggravate metabolic dysfunction. These changes indicate that adipose tissue–liver crosstalk is a key mechanism linking PCOS and MetS. Overall, metabolic disturbances in PCOS are strongly mediated by dysregulated communication between adipose tissue and the liver. Altered hepatokine and adipokine profiles contribute to insulin resistance, liver dysfunction, hypertension and the development of MetS in women with PCOS. Understanding these intricate interactions may support the early identification of high-risk patients and the development of targeted therapeutic strategies. Full article

Spondyloarthritis represents a group of chronic immune-mediated rheumatic diseases that manifest as peripheral or axial musculoskeletal involvement. In axial spondyloarthritis (axSpA), the milestones of structural damage are represented by inflammation, followed by erosions in the sacroiliac joints (SIJ) and new bone formation. The purpose of this narrative review is to address the unmet needs regarding targeted risk stratification of disease progression in axSpA. While studies concerning predictive biomarkers have been conducted, their use in clinical practice has not yet been validated. Analysis of disease progression in patients recently diagnosed with non-radiographic axSpA, with fulfillment of the Assessment of Spondyloarthritis International Society criteria, determined a mean time of structural changes progression of 2.4 years. While factors such as human leukocyte antigen (HLA)-B27 and C-reactive protein are useful in classifying patients into risk categories regarding radiographic progression, novel biomarkers are needed in clinical practice to further facilitate treatment strategy selection. Choosing biomarkers to analyze the potential of both spinal and SIJ radiographic progression is useful in monitoring patients and reducing the burden of disease. Fetuin-A, sclerostin, and autoantibodies against Cluster of Differentiation 74 (anti-CD74) were associated with SIJ changes in various studies. Regarding spinal structural damage, adipokines, particularly leptin and visfatin, have been extensively studied and have shown promising results. Dickkopf-1, a regulator of the Wnt signaling pathway, vascular endothelial growth factor, and matrix metalloproteinase-3 have also presented associations with worsening modified Stoke Ankylosing Spondylitis Spine Score. The potential of each biomarker may be heightened by their use in prediction models with the purpose of implementation in clinical practice, particularly in improving patient outcomes and tailoring treatment strategies for individuals with spinal structural damage. Full article

Breast cancer remains the most frequently diagnosed malignancy among women worldwide, while metabolic dysfunction-associated steatotic liver disease (MASLD) represents the leading cause of chronic liver disease, reflecting a global burden of metabolic dysfunction. Increasing evidence suggests that MASLD is associated with breast cancer development and progression; however, whether this relationship reflects an independent effect of hepatic metabolic dysfunction or the broader metabolic environment remains uncertain. This review synthesizes current epidemiological, clinical, and mechanistic data linking hepatic metabolic dysfunction to breast carcinogenesis. Population-based studies consistently demonstrate an association between hepatic steatosis and increased breast cancer incidence, particularly in postmenopausal and metabolically vulnerable populations, as well as poorer oncological outcomes. Mechanistically, MASLD promotes a systemic pro-tumorigenic environment through interconnected pathways, including insulin resistance, hormonal dysregulation with increased estrogen bioavailability, chronic inflammation, oxidative stress, lipid metabolic reprogramming, and gut–liver axis disruption. Hepatokines, particularly fibroblast growth factor 21 (FGF21), emerge as key mediators of tumor progression and potential biomarkers of metabolic vulnerability, while Fetuin-A and angiopoietin-like protein 8 (ANGPTL8) further support the liver’s endocrine role in oncogenic signaling. Preclinical evidence highlights fatty acid oxidation as a metabolic dependency in aggressive breast cancer subtypes, suggesting novel therapeutic targets. Despite consistent associations, causality remains unproven. Future prospective studies are needed to determine whether targeting metabolic dysfunction can improve breast cancer prevention and outcomes. Full article

Background/Objectives: Cardiovascular disease (CVD) in chronic kidney disease (CKD) arises from a multifaceted interplay of pathophysiological processes, including chronic inflammation, oxidative stress (OS), and accelerated vascular calcification (VC). Red blood cell distribution width (RDW) and the neutrophil-to-lymphocyte ratio (NLR) have emerged as simple, inexpensive, and readily available hematological indices that may capture these underlying disturbances. As such, they hold promise as accessible biomarkers for stratifying cardiovascular risk in patients with CKD. Methods: This cross-sectional study enrolled 497 patients, comprising 477 with CKD across all stages and 20 controls. We evaluated the associations of RDW and NLR with both traditional and non-traditional cardiovascular risk factors, as well as with serum calcification propensity (T50). Spearman’s correlation and multivariable regression analysis were used to assess these relationships. Results: Both RDW and NLR were significantly elevated in patients with established CVD (p < 0.001 for both) and demonstrated a progressive increase across advancing CKD stages (p < 0.001). RDW and NLR showed positive correlations with age, CVD duration, urea, phosphorus, parathormone, CRP, FG23, and mean carotid intima–media thickness (cIMT), while exhibiting inverse correlations with eGFR, serum albumin, hemoglobin, lipids, antioxidants such as superoxide dismutase, fetuin-A, and T50. Additionally, NLR correlated positively with the duration of hypertension and diabetes, as well as with albuminuria. Quartile analysis revealed a stepwise decline in T50 across increasing categories of RDW and NLR, supporting the link with impaired calcification defense. In multivariable analysis, T50 independently predicted NLR (β = −0.013; p = 0.018), whereas total cholesterol (β = −0.011; p = 0.019) and cIMT (β = 0.38; p = 0.018) emerged as independent determinants of RDW. Conclusions: RDW and NLR strongly reflect the burden of inflammation, metabolic disturbance, and vascular dysfunction in patients across the CKD spectrum. The consistent associations with impaired calcification defense and with established cardiovascular risk markers underscore the potential value as accessible indicators of cardiovascular vulnerability in CKD. These findings support incorporating RDW and NLR into routine risk assessment and highlight T50 as a mechanistically relevant determinant of hematologic inflammation profiles. Full article

Metabolic inflammation, a state of chronic low-grade inflammation linked to insulin resistance, plays a central role in the development of obesity-related conditions such as type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disorders. In recent years, two molecules have gained significant prominence in this field, owing to their mechanistic involvement in metabolic inflammation and insulin resistance: fetuin-A (FetA), aliver-derived hepatokine, and chymase, a serine protease released from mast cells. Although they arise from distinct biological sources, they converge on overlapping inflammatory and metabolic pathways. FetA acts as an endogenous ligand for Toll-like receptor 4 (TLR4), activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, driving proinflammatory cytokine release, and impairing insulin signaling. Chymase, on the other hand, generates angiotensin II and activates transforming growth factor-β (TGF-β), thereby promoting oxidative stress, fibrosis, and secondary metabolic dysfunction. This review proposes a conceptual dual-target framework in which FetA and chymase are considered complementary, rather than independent, mediators of metabolic inflammation. Importantly, this framework is not intended to supersede other established pathways implicated in metabolic inflammation, but rather to provide an integrative perspective that complements existing hepatokine and immune-centered models. Their convergence on NF-κB and TGF-β signaling pathways highlights shared mechanistic nodes within metabolic inflammation. Accordingly, the emphasis of this review is on mechanistic integration within metabolic inflammation, rather than on immediate therapeutic innovation or clinical translation. Full article

This paper aims to examine the current landscape of novel biomarkers in diabetes mellitus (DM), with particular emphasis on emerging candidates, and their roles in early diagnosis, monitoring disease progression, risk stratification, and managing complications. Given the global prevalence of DM and its complex pathophysiology, identifying reliable biomarkers is critical for optimizing prevention strategies and personalized treatment approaches. This review highlights the shift from traditional glycemic markers, which remain clinically useful but limited, to a broader array of novel biomarkers that more accurately reflect the complex pathophysiology of DM. In addition to conventional measures, inflammatory and oxidative stress mediators, along with genetic and epigenetic regulators, provide added predictive value for disease susceptibility, progression, and complications. Recent research has identified emerging biomarkers, such as adiponectin, adropin, netrin-1, α-hydroxybutyrate, fetuin-A, lipo-protein(a), and lysophosphatidylcholine, which detect early metabolic imbalances and reveal mechanistic links to insulin resistance, β-cell dysfunction, and vascular injury. Their integration into multimarker panels holds particular promise for precision medicine, supporting tailored prevention, targeted therapy, and improved outcomes for individuals with prediabetes and DM. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic condition with a complex pathophysiology involving multiple organs. Organokines, including hepatokines, myokines, cardiokines, renokines, osteokines, and adipokines, play central roles in lipid metabolism, glucose homeostasis, inflammation, and fibrosis. Dysregulation of these signaling molecules contributes to the progression of MASLD and its systemic complications. This review examines the role of organokine-mediated crosstalk between the liver and peripheral organs (e.g., muscle, heart, kidneys, bone, and adipose tissue) in the pathogenesis of MASLD. Key molecules, such as myostatin, FGF-21, IL-6, and adiponectin, influence insulin sensitivity, lipid metabolism, and inflammation. Some organokines have protective effects (e.g., FGF-21, irisin, and klotho), while others, such as myostatin and fetuin-A, exacerbate insulin resistance and fibrosis. These findings suggest that targeting organokines could provide potential biomarkers and therapeutic strategies for MASLD. Future research should focus on elucidating the molecular mechanisms and assessing the role of organokines in the prevention and treatment of MASLD. Full article

Due to their prevalence, diabetes and its complications continue to pose a significant challenge in modern medicine. It is particularly important to identify and develop new biomarkers that would enable faster and more effective detection of specific diseases, including the most common complication of diabetes—diabetic kidney disease (DKD). This review presents the current knowledge on two proteins—fetuin-A and heme oxygenase 1 (HO-1)—whose biological functions and involvement in the pathophysiology of the discussed disease make them potentially useful biomarkers. Moreover, there are studies indicating an association of polymorphisms in the genes encoding fetuin-A and HO-1 with the risk of developing diabetes or DKD. Based on the available literature, both proteins appear promising for use in the diagnosis of diabetes and its complications or assessing the risk of these diseases. However, this requires confirmation in large-scale studies and the development and standardization of detection methods. Full article

Background/Objectives: Fetuin-A is a multifunctional glycoprotein involved in metabolic and inflammatory regulation. Although its role in insulin resistance, type 2 diabetes, and cardiovascular disease is well recognized, its relationship with pregnancy-related body mass changes remains unclear. This study aimed to explore associations between maternal BMI dynamics during and shortly after pregnancy and serum fetuin-A concentrations. Methods: Fifty-five healthy Caucasian women with term singleton pregnancies were enrolled. BMI was recorded at three time points: pre-pregnancy, before delivery, and 48 h postpartum. Based on ΔBMI (postpartum minus pre-pregnancy BMI), participants were divided into two groups: ΔBMI ≤ 1 kg/m² (n = 32) and ΔBMI > 1 kg/m² (n = 23). Serum fetuin-A levels were measured before delivery and postpartum using ELISA. Additional laboratory parameters and body composition were assessed postpartum via standard tests and bioelectrical impedance analysis (BIA). Results: No significant differences were found between groups in BMI at any single time point or in laboratory or BIA-derived parameters. However, all three BMI change indices (ΔBMI_gestational, ΔBMI_puerperal, and ΔBMI) differed significantly between groups. Fetuin-A concentrations did not differ significantly between groups. Importantly, fetuin-A levels decreased significantly after delivery in both groups, suggesting a potential role of the placenta in its regulation. A significant correlation was observed between pre-delivery fetuin-A and postpartum uric acid in Group ΔBMI > 1 kg/m² (p = 0.016), indicating a possible link in women with greater gestational weight gain. Conclusions: While fetuin-A was not directly associated with BMI changes, its peripartum dynamics and correlation with uric acid may reflect underlying metabolic-inflammation pathways. ΔBMI indices may offer a more individualized measure of weight dynamics in pregnancy research. Full article

The incidence and prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing, and, currently, the disease affects approximately 30% of the global population. Therefore, there is a growing need for widely available, patient-friendly, and reliable diagnostic tools. Our review is focused on the presentation and discussion of emerging biomarkers for evaluation and non-invasive detection of liver fibrosis in patients with MASLD, including glycation markers (AGEs/sRAGE), lipid mediators (eicosanoids), fetuin-A, collagen turnover markers (PRO-C3, ADAPT), and omic-based technologies. As reported recently, some of these parameters revealed high diagnostic accuracy in clinical trials, so they may be incorporated as key diagnostic tools in the future MASLD approach. Employment of such biomarkers may enable correct and quick identification of MASLD and/or MASH patients, as well as better monitoring of their treatment response. The development of precision medicine, driven by multiomics and individualized profiling, promises a rearrangement from the traditional “one size fits all” to tailoring targeted care, as environmental factors may have an even more relevant impact on MASLD pathogenesis in comparison with genetic predisposition. Nevertheless, to enable their widespread clinical use, novel biomarkers require further rigorous validation and standardized implementation in healthcare settings. Full article

Background: Fetuin-A, a hepatokine implicated in metabolic regulation, has been associated with both metabolic syndrome and cardiovascular disease. However, its specific role in type 2 diabetes mellitus (T2DM) remains incompletely understood. Objective: This study aimed to investigate the relationship between fetuin-A levels and key components of metabolic syndrome (abdominal obesity, arterial hypertension, hyperglycemia, hypertriglyceridemia and low high-density lipoprotein cholesterol) as well as other cardiovascular risk markers, including metabolic dysfunction-associated fatty liver disease (MAFLD), carotid intima-media thickness (CIMT), and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Methods: A total of 51 patients with T2DM not receiving insulin therapy were enrolled. Participants underwent clinical, biochemical, and imaging evaluations. Hepatic steatosis was assessed via abdominal ultrasonography, and subclinical atherosclerosis was evaluated using CIMT measured with Doppler ultrasonography. Serum fetuin-A was quantified by ELISA. Results: Hepatic steatosis was significantly associated with metabolic syndrome, increased CIMT, and dyslipidemia (elevated total cholesterol, triglycerides, and reduced HDL cholesterol). Although no direct correlation was found between fetuin-A levels and hepatic steatosis, multivariate analysis revealed that fetuin-A concentrations were significantly influenced by total cholesterol and LDL cholesterol levels. Conclusions: Fetuin-A appears to be linked to lipid abnormalities in T2DM and may contribute to cardiovascular risk in this population. These findings support the potential utility of fetuin-A as a biomarker and possible therapeutic target for dyslipidemia management in diabetic patients. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health challenge characterized by complex adipose–liver interactions mediated by adipokines and hepatokines. Despite rapid field evolution, a comprehensive understanding of research trends and translational advances remains fragmented. This study systematically maps the scientific landscape through bibliometric analysis, identifying emerging domains and future clinical translation directions. Methods: A comprehensive bibliometric analysis of 1002 publications from 2004 to 2025 was performed using thematic mapping, temporal trend evaluation, and network analysis. Analysis included geographical and institutional distributions, thematic cluster identification, and research paradigm evolution assessment, focusing specifically on adipokine–hepatokine signaling mechanisms and clinical implications. Results: The United States and China are at the forefront of research output, whereas European institutions significantly contribute to mechanistic discoveries. The thematic map analysis reveals the motor/basic themes residing at the heart of the field, such as insulin resistance, fatty liver, metabolic syndrome, steatosis, fetuin-A, and other related factors that drive innovation. Basic clusters include metabolic foundations (obesity, adipose tissue, FGF21) and adipokine-centered subjects (adiponectin, leptin, NASH). New themes focus on inflammation, oxidative stress, gut microbiota, lipid metabolism, and hepatic stellate cells. Niche areas show targeted fronts such as exercise therapies, pediatric/novel adipokines (chemerin, vaspin, omentin-1), and advanced molecular processes that focus on AMPK and endoplasmic-reticulum stress. Temporal analysis shows a shift from single liver studies to whole models that include the gut microbiota, mitochondrial dysfunction, and interactions between other metabolic systems. The network analysis identifies nine major clusters: cardiovascular–metabolic links, adipokine–inflammatory pathways, hepatokine control, and new therapeutic domains such as microbiome interventions and cellular stress responses. Conclusions: In summary, this study delineates current trends and emerging areas within the field and elucidates connections between mechanistic research and clinical translation to provide guidance for future research and development in this rapidly evolving area. Full article

Vitamin D deficiency is highly prevalent in individuals with overweight/obesity and this can be largely attributed to the entrapment of VitD in adipose tissue due to impaired lipolytic stimulation. Considering the well-described role of exercise in stimulating lipolysis, the present study investigated the efficacy of multicomponent-type high-intensity interval training (m-HIIT) in increasing 25-hydroxyvitamin D [25(OH)D] levels in males with overweight/obesity. Twenty middle-aged males (43.5 ± 5 years, BMI: 30.7 ± 3.3 kg/m²) participated in three weekly supervised m-HIIT sessions over a 12-week period and underwent assessments at baseline, 6, and 12 weeks. Primary outcomes were total body fat mass, android fat, hepatorenal index, and serum 25(OH)D. Participants’ daily physical activity and dietary intake habits remained unaltered throughout the 12-week training period. The m-HIIT intervention reduced fat mass (by 3% at 12 weeks), android fat (by 3.7% at 6 weeks and 4.4% at 12 weeks), and hepatorenal index (by 8% at 12 weeks). Serum 25(OH)D levels increased by ~14% (+3.21 ng/mL, p = 0.002) and ~31% (+7.24 ng/mL, p < 0.001) at 6 and 12 weeks, respectively. The elevation of 25(OH)D levels at 12 weeks was inversely related to fat mass loss (R = 0.53, p = 0.016). Plasma SGPT, SGOT, ALP, γ-GT, fetuin-A, and calcium levels remained unaltered after the 12-week training period. In conclusion, m-HIIT may be useful as a non-pharmacological intervention to increase circulating VitD levels in adults with overweight/obesity. Full article

Background and Objectives: Fetuin-A is mostly synthesized in the liver. It is a hepatokine, which is an extracellular inhibitor of growth factors. There is a scarcity of data on the clinical utility of serum fetuin-A (SFA) in alcohol-associated cirrhosis (AC). We first investigated the association between SFA levels and disease phenotypes in alcoholic liver disease (ALD) patients, including alcohol-associated steatotic liver (ASL) and alcohol-associated hepatitis (AH), along with AC patients. Materials and Methods: There were 26 healthy controls and 64 ALD patients in this case–control study. The severity of the disease in the AC patients was evaluated using the Child–Pugh classification (CPC-A, -B, and -C), and the FH and AC patients’ Maddrey’s differential function scores and the Model of End-Stage Liver Disease Sodium (MELD-Na) scores were computed. We measured SFA levels using a human fetuin-A enzyme-linked immunosorbent assay (ELISA) kit. Results: The SFA concentrations were lower in the AC group and higher in the ASL group [670.72 (412.36) mg/L vs. 1484.61 (858.16) mg/L, respectively; p < 0.001]. When compared to patients with ASL, the SFA levels in AC patients were noticeably lower. However, similar SFA levels were observed for the AH group and the healthy controls, as well as for the ASL group and the healthy controls. Within the AC group, the CPC-A subgroup had the highest median SFA values, while the CPC-C subgroup had the lowest median SFA value. Furthermore, the median SFA levels demonstrated significant and inverse correlations with the CPC scores and the MELD-Na scores (rho = −0.671, p < 0.001; rho = −0.742, p < 0.001, respectively). A negative correlation was observed between the SFA levels and the MELD-Na scores in the AH group (ρ = −0.621, p = 0.013). Conclusions: In ALD patients, decreased SFA levels, which exhibit disease severity, might be an auxiliary biomarker for the follow-up of AC patients. Full article