Search Results (262)

Background/Objectives: We aimed to establish and validate population-based reference intervals (RIs) for serum ferritin (SF) using an indirect, date-driven approach based on real-world laboratory data and to optimize partitioning strategies. Methods: SF results from 29,723 apparently healthy individuals who underwent health examinations at West China Hospital between 2020 and 2024 were retrospectively analyzed. SF was measured on a Roche Cobas e801 electrochemiluminescence immunoassay platform. After Box–Cox transformation, outliers were removed using an iterative Tukey method. Potential partitioning factors were evaluated, and data-driven age cut-points were explored using decision tree regression and verified with the Harris–Boyd criteria. RIs were estimated using nonparametric percentile methods and validated in an independent cohort of 2494 individuals. Results: SF concentrations were significantly higher in males than in females (p < 0.001). In females, SF showed a significant positive association with age (r = 0.466, p < 0.001), whereas no such association was observed in males. Decision tree analysis identified 50 years as the optimal age cut-off for females (R² = 0.2467). The final study-derived RIs were 98.02–997.78 µg/L for males, 10.30–299.55 µg/L for females ≤ 50 years, and 36.61–507.00 µg/L for females > 50 years. In the validation cohort, the study-derived RIs achieved pass rates of 93.83–94.72%, which were significantly higher than the manufacturer-provided RIs (37.12–73.97%, all p < 0.001). Conclusions: Using a large health examination database and a multi-step partitioning strategy, we established robust sex- and age-specific SF RIs on the Roche Cobas e801 platform for the local population. This work provides a reproducible, generalizable framework for indirect RI determination of other biomarkers. Full article

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia worldwide and is now increasingly regarded as a disease of chronic inflammation and progressive atrial fibrosis. Understanding of molecular mechanisms that mediate the linkage between systemic metabolic dysregulation, inflammation, and structural atrial changes is crucial for informing risk stratification and targeting of prevention strategies. This review provides evidence from 105 studies focusing on the contributions of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-a (TNF-α), interleukin-6 (IL-6), galectin-3, and galectin-1 to cardiac fibrogenesis, atrial fibrosis, and AF pathogenesis. We also link metabolic syndrome to these biomarkers and to atrial remodeling, as well as echocardiographic correlates of fibrosis. TGF-β1 is established as the central profibrotic cytokine and promotes Smad-based fibroblast activation, collagen accumulation, and structural atrial remodeling. Its role is highly potentiated by thrombospondin-1 by turning latent TGF-β1 into its potent form. TNF-α and IL-6 also play an integral role in the inflammatory fibrotic continuum by activating NF-κB and STAT3 signaling, promoting fibroblast proliferation, electrical uncoupling, and extracellular matrix accumulation. Galectin-3 is a potent profibrotic mediator that promotes TGF-β signaling and is a risk factor for negative outcomes, whereas Gal-1 seems to regulate inflammation resolution and may exert context-dependent protective or maladaptive roles. Metabolic syndrome is strongly associated with excessive levels of these biomarkers, chronic low-grade inflammation, oxidative stress, and ventricular and atrial fibrosis. Chronic clinical findings show that metabolic syndrome (MetS) increases AF risk, exacerbates atrial dilatation, and is associated with worse postoperative outcomes. Echocardiographic data are connected to circulating biomarkers and are non-invasive for evaluating atrial remodeling. The evidence to date supports that atrial fibrosis should be considered an end point of systemic inflammation, metabolic dysfunction, and activation of profibrotic molecular pathways. Metabolic syndrome, due to its chronic low-grade inflammatory environment and prolonged levels of metabolic stress, manifests as an important upstream factor of fibrotic remodeling, which continuously promotes the release of cytokines, oxidative stress, and fibroblast activation. Circulating fibrotic biomarkers, in comparison with metabolic syndrome, serve separate yet interdependent pathways that help orchestrate atrial structural remodeling through the simultaneous process but can also provide a long-term indirect measure of ongoing profibrotic activity. The integration of these biomarkers with superior atrial imaging enables a broader understanding of the fibrotic substrate of atrial fibrillation. This combined molecular imaging approach can facilitate risk stratification, refine therapeutic decisions, and facilitate early identification of higher-risk metabolic phenotypes, thus potentially facilitating directed antifibrotic and anti-inflammatory therapy in atrial fibrillation. Full article

Background: Sarcoidosis is a heterogeneous, multisystem inflammatory disease with an unpredictable clinical course and limited prognostic markers. Increasing attention has focused on nutritional and metabolic factors—particularly obesity, body composition, and calcium–vitamin D metabolism—as potentially modifiable elements associated with disease development and clinical phenotype. However, the available literature remains fragmented and methodologically heterogeneous. Objective: To systematically map current evidence on the relationship between nutritional status and the development, clinical course, and prognosis of sarcoidosis, and to identify key gaps requiring further research. Methods: A scoping review was conducted in accordance with the Joanna Briggs Institute methodology and the PRISMA-ScR guidelines. PubMed, Scopus, Web of Science, Cochrane Library, EBSCO, and Google Scholar were searched for studies published between 2015 and 2025. Eligible studies included adult patients with sarcoidosis and addressed nutritional status broadly defined, encompassing anthropometric measures, body composition, immunonutritional indices, nutrition-related biomarkers, dietary factors, and supplementation practices. Due to substantial heterogeneity in exposure definitions and outcome measures, no quantitative synthesis or formal methodological quality appraisal was performed. Results: Eighteen studies, predominantly observational, were included. The most consistent findings concerned anthropometric parameters, with overweight and obesity showing the strongest association with an increased risk of sarcoidosis and, in selected studies, with reduced exercise capacity and greater disease burden. Evidence linking nutritional status to prognosis was indirect, while direct data on sarcoidosis-specific survival were lacking. Disturbances in calcium–vitamin D metabolism were frequent and clinically relevant, particularly in the context of supplementation-related hypercalcemia. Conclusions: Current evidence suggests that nutritional status—particularly excess body weight—and selected metabolic and immunonutritional factors are associated with sarcoidosis. However, given the largely observational nature of the available data and the lack of formal assessment of methodological quality, these results should be interpreted as association mapping and hypothesis generation rather than as evidence of causality. Well-designed prospective and interventional studies using standardized nutritional assessment tools and clinically relevant endpoints are needed to clarify the role of nutritional factors in sarcoidosis. Full article

COVID-19 has raised significant concern regarding its neurological impact, particularly during the early pandemic waves when severe systemic inflammation and neuroimmune dysregulation were more common. Although SARS-CoV-2 has been extensively studied, the precise mechanisms underlying its neurological effects remain incompletely understood, and much of the available evidence is derived from early variants with higher pathogenicity. Current research indicates that neuroinflammatory processes—driven primarily by systemic cytokine elevation, microglial activation, and blood–brain barrier dysfunction—contribute to a wide range of neurological symptoms. Severe complications such as encephalopathy, stroke, and cognitive impairment were predominantly reported in critically ill patients infected with the Wuhan, Alpha, or Delta variants, while such manifestations are considerably less frequent in the Omicron era. Most proposed mechanisms, including ACE2-mediated viral entry into the central nervous system, are supported mainly by experimental or preclinical studies rather than definitive human evidence. Biomarkers such as IL-6 and TNF-α, along with neuroimaging modalities including MRI and PET, offer useful but indirect indicators of neuroinflammation. Therapeutic approaches continue to focus on controlling systemic inflammation through immunomodulatory agents, complemented by targeted non-pharmacological strategies—such as physical rehabilitation, cognitive support, and psychological interventions—for the minority of patients with persistent neurological deficits. Overall, current evidence supports a variant-dependent neuroinflammatory profile and underscores the need for longitudinal, mechanism-focused studies to better characterize long-term neurological outcomes and refine therapeutic strategies. Full article

Background: The clinical–radiological paradox in multiple sclerosis (MS) underscores the need for biomarkers that better reflect neurodegenerative pathology. Serum neurofilament light chain (sNfL) is a dynamic marker of neuroaxonal injury, while brain volumetry provides structural assessment of disease impact. However, the precise link between sNfL and regional atrophy patterns, as well as their combined utility for patient stratification and prediction, remains underexplored. Objective: This study aimed to establish a multimodal biomarker framework by integrating sNfL with comprehensive volumetric MRI to define neurodegenerative endophenotypes and predict neuroaxonal injury using Bayesian inference and machine learning. Methods: In a cohort of 57 MS patients, sNfL levels were measured using single-molecule array (Simoa) technology. Brain volumes for 42 regions were quantified via automated deep learning segmentation (mdbrain software). We employed (1) Bayesian correlation to quantify evidence for sNfL–volumetric associations; (2) mediation analysis to test whether grey matter atrophy mediates the EDSS–sNfL (Expanded Disability Status Scale) relationship; (3) unsupervised K-means clustering to identify patient subtypes based on combined sNfL–volumetric profiles; and (4) supervised machine learning (Elastic Net and Random Forest regression) to predict sNfL from volumetric features. Results: Bayesian analysis revealed strong evidence linking sNfL to total grey matter volume (r = −0.449, BF₁₀ = 0.022) and lateral ventricular volume (r = 0.349, BF₁₀ = 0.285). Mediation confirmed that grey matter atrophy significantly mediates the relationship between EDSS and sNfL (indirect effect = 0.45, 95% CI [0.20, 0.75]). Unsupervised clustering identified three distinct endophenotypes: “High Neurodegeneration” (elevated sNfL, severe atrophy, high disability), “Moderate Injury,” and “Benign Volumetry” (low sNfL, preserved volumes, mild disability). Supervised models predicted sNfL with high accuracy (R² = 0.65), identifying total grey matter volume, ventricular volume, and age as top predictors. Conclusions: This integrative multi-method analysis demonstrates that sNfL is robustly associated with global grey matter and ventricular volumes, and that these measures define clinically meaningful neurodegenerative subtypes in MS. Machine learning confirms that a concise set of volumetric features can effectively predict neuroaxonal injury. These findings advance a pathobiology-driven subtyping framework and provide a validated model for using routine MRI volumetry to assess neuroaxonal health, with implications for prognosis and personalised therapeutic strategies. Full article

Steatotic liver disease (SLD) represents a major global health burden, with environmental toxicants emerging as critical contributors alongside metabolic dysfunction. Bisphenol F (BPF), an increasingly prevalent replacement for bisphenol A, is widely detected in human biological samples and environment, yet its hepatotoxic mechanisms remain incompletely characterized. This review synthesizes current evidence on BPF-induced SLD, with a particular focus on resolving the “pregnane X receptor (PXR) paradox”, the mismatch between BPF’s weak direct activation of PXR and the PXR-like metabolic effects observed in vivo. Comprehensive analysis of mechanistic pathways reveals that BPF-induced SLD develops predominantly through PXR-independent mechanisms involving oxidative stress, endoplasmic reticulum dysfunction, Drp1-mediated mitochondrial fission, NLRP3/NF-κB-driven inflammation, dysregulated post-translational modifications, and epigenetic remodelling. These converging pathways collectively disrupt hepatic lipid metabolism, promote triglyceride accumulation, and establish a self-perpetuating cycle of metabolic dysfunction. Notably, weak indirect PXR modulation via oxidative stress represents a secondary, non-causal mechanism unsupported by functional validation. This framework distinguishes toxicant-induced steatosis from metabolic dysfunction-associated steatotic liver disease while highlighting critical evidence gaps—particularly the absence of causal PXR validation studies and human epidemiological data. Therapeutic opportunities exist at validated convergence points including mitochondrial dynamics (Drp1), inflammatory signalling (NLRP3/NF-κB), and energy metabolism (AMPK-mTOR), though combination strategies targeting multiple pathways will likely be required for durable disease reversal. These findings necessitate the expansion of regulatory screening paradigms to incorporate cellular stress pathway biomarkers alongside traditional nuclear receptor endpoints, ensuring comprehensive hepatotoxic risk assessment of emerging BPA substitutes. Full article

Cardiovascular–kidney–metabolic syndrome (CKMS) represents the intricate interconnection of cardiovascular, kidney, and metabolic disorders, with systemic inflammation now recognized as a key driver of both pathogenesis and prognosis. This systematic review aimed to synthesize current evidence on the prognostic value of inflammatory biomarkers in individuals with CKMS. A systematic search of PubMed, Embase, CINAHL, Web of Science, and Scopus were conducted to identify studies published between 1 January 2024 and 30 June 2025, following the recognition of CKMS as a distinct syndrome in December 2023. Eligible studies included adults (aged ≥ 18 years) with CKMS, that assesses one or more inflammatory markers and reported prognostic outcomes such as mortality or disease progression. Data extracted included study characteristics, biomarker types, outcome measures, and key findings. In addition to longitudinal cohorts, we included a small number of cross-sectional studies and treated them as association (non-prognostic) evidence analyzed in a separate stream from prognostic cohorts. Risk of bias was evaluated using the Quality in Prognostic Studies (QUIPS) tool. Due to considerable variability in prognostic outcomes, follow-up durations, and inflammatory indices, a meta-analysis was not feasible. Instead, a narrative synthesis was undertaken to summarize the evidence, identify consistent associations, and emphasize the need for standardized approaches and biomarker validation in future CKMS research. Analysis was conducted in line with the SWiM guidelines. Thirteen studies (n = 13) comprising 282,016 participants (100,590 males; 97,295 females) were included from 1404 initial records. Five of the studies were cross-sectional, providing information on associations rather than prognostic outcomes. Most were large-scale cohort studies conducted in the USA and China. Frequently assessed biomarkers included systemic inflammatory response index (SIRI), systemic immune-inflammation index (SII), high-sensitivity C-reactive protein to high-density lipoprotein cholesterol ratio (hs-CRP/HDL-C), dietary inflammatory index (DII), and triglyceride–glucose (TyG) index. Elevated levels of these biomarkers were consistently associated with higher risk of all-cause and cardiovascular mortality, CKMS progression, and adverse metabolic outcomes. This review highlights systemic inflammation as a critical and associated marker of CKMS prognosis. Inflammatory biomarkers may assist in hypothesis generation, but clinical utility remains to be established pending standardized adjustment and external validation. Because CKMS has only recently been operationalized, we limited inclusion to studies published from 1 January 2024 onward, enhancing definitional comparability but narrowing the evidence base and potentially emphasizing early-adopter regions (predominantly the U.S. and China). Accordingly, these findings should be interpreted as early signals that require replication in diverse settings and confirmation through longitudinal and interventional studies to inform integrative CKMS management strategies. Across observational studies, the certainty of evidence is low to moderate due to indirectness and imprecision; findings should be treated as associational signals pending external validation. Full article

Acute myocardial infarction (AMI) is a rapidly progressing cardiovascular condition associated with high mortality. Myoglobin is an early biomarker of AMI; however, its detection using conventional methods is limited by complex workflows and low resistance to interference. In this study, we developed an integrated myoglobin detection platform that combined magneto-immunoassay with microfluidic technology. A giant magnetoresistance (GMR) sensor was fabricated using micro-electro-mechanical systems (MEMS). The designed microfluidic chip integrated sample pretreatment, immunoreaction, and magnetic signal capture functionalities. Its built-in GMR sensor, labeled with magnetic nanoparticles, directly converted the “antigen–antibody” biochemical signal into detectable magnetoresistance changes, thereby enabling the indirect detection of myoglobin. A magneto-immunoassay analysis system consisted of a fluidic drive, magnetic field control, and data acquisition functions. Various key parameters were optimized, including EDC/NHS concentration, antibody concentration, and magnetic bead size. Under the optimal conditions and using 1 μm magnetic beads as labels and an external detection magnetic field of 60 Oe, the platform successfully detected myoglobin at 75 ng/mL with ∆MR ≥ 0.202%. Specificity tests demonstrated that the platform had high specificity for myoglobin and could effectively distinguish myoglobin from bovine serum albumin (BSA) and troponin I. This study presents a rapid, accurate myoglobin detection platform that can be applied for the early diagnosis of AMI. Full article

Background/Objectives: Cytochrome P450 (CYP) enzymes are crucial for drug metabolism, yet inter-individual variability in their activity remains a significant clinical challenge. Current phenotyping methods are often impractical or even impossible, particularly in forensic toxicology and vulnerable populations. This proof-of-concept study investigated the feasibility of using in vitro assays with human liver microsomes (HLM) and recombinant CYP enzymes (isoenzymes), combined with untargeted metabolomics, to identify potential endogenous biomarker candidates indicative of CYP phenotype. Methods: This study uses in vitro incubations of HLM and isoenzymes in tandem with targeted and untargeted LC-(HR)MS and metabolomics techniques as well as statistical processing. Results: We demonstrate that HLM and isoenzymes maintain activity in the presence of complex biological matrices (blood/plasma), enabling metabolomic profiling. Untargeted analysis of assays in plasma revealed numerous potential biomarkers, with several showing significant correlations to enzyme activity. Conclusions: While identification remains the major challenge, this approach offers a promising avenue for developing accessible and efficient methods for indirect CYP phenotyping, potentially facilitating investigations in scenarios where traditional approaches are limited. This work provides a foundation for future studies focused on further developing in vitro assays and validating the proposed biomarkers, as well as establishing their utility in clinical and forensic settings. Full article

The development of new approach methodologies that include human cells differentiated into organotypic formats is of high interest due to their structural and functional similarities to tissues in vivo, enabling mechanistic understanding and translation to adverse health outcomes in humans. However, these systems often fail to capture complex intercellular signaling required for processes such as pulmonary inflammation induced by polycyclic aromatic hydrocarbons (PAHs). To investigate airway epithelial–macrophage interactions in response to benzo[a]pyrene and a PAH mixture (Tox Mix), co-culture models utilizing primary human bronchial epithelial cells (HBECs) differentiated at the air–liquid interface were cultured with THP-1 macrophages either directly or indirectly, alongside HBECs alone. After 24 h of exposure, cytokine expression (IL1B, IL6, CXCL8, TNF) as well as PAH biomarkers previously identified for chemical metabolism (CYP1A1, CYP1B1), oxidative stress (ALDH3A1, HMOX1, NQO1), and barrier integrity (TJP2) were evaluated. Cytotoxicity and barrier integrity were also assessed. HBECs alone and direct co-cultures exhibited similar responses after PAH treatment, while indirect co-cultures showed lower sensitivity to induction of inflammatory cytokines and CYP1A1 and CYP1B1 biomarker expression following exposure to PAHs. The expression of other biomarkers, including ALDH3A1, HMOX1, and NQO1, remained largely consistent across all models after treatment. Overall, these findings suggest that direct co-culture systems may provide a more physiologically relevant platform for studies of PAH-induced toxicity and demonstrate that the configuration of co-culture systems can influence cellular responses to chemical exposure. Full article

Cancer is the disease found to be the reason for the largest portion of deaths in the world annually and these mortality values are expected to increase in the future. Early detection of cancer biomarkers may help save millions of lives, particularly by implementing non-invasive and economical detection methods. In this review, we tabulated and quantitatively compared the data collected in 173 rows from 124 publications, which describe the clinical application of various methods in detection of cancer biomarkers. Those methods include mass spectrometry (MS), immunoassays (IAs), enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), surface-enhanced Raman spectroscopy (SERS), and Fourier-transform infrared spectroscopy (FTIR). We found that direct methods may have an advantage over indirect methods. Direct SERS reported in clinical applications can also achieve a higher area under the curve, higher sensitivity, and specificity than those parameters for ELISA, PCR, MS, and FTIR applications. Based on the average area under the curve (AUC) values reported in the last 6–7 years for each method, the performance of the analytical methods for the clinical cancer detection increases from IAs (0.76), ELISA (0.83), MS (0.87), and PCR (0.89) to FTIR (0.95) and SERS (0.97). Full article

Hypertrophic cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disorder characterized by unexplained left ventricular hypertrophy, sarcomeric hypercontractility, and dynamic left ventricular outflow tract (LVOT) obstruction in approximately 70% of patients. Current therapies predominantly offer symptomatic relief through indirect modulation of cardiac function, leaving the underlying molecular pathophysiology unaddressed. Mavacamten, a first-in-class, selective allosteric inhibitor of β-cardiac myosin ATPase, exemplifies a precision pharmacological approach by directly targeting the sarcomeric hypercontractility fundamental to obstructive HCM (oHCM). This review synthesizes extensive clinical and preclinical evidence delineating mavacamten’s mechanism of action, pharmacokinetics influenced by CYP2C19 genotype variability, and its demonstrated efficacy and long-term safety in improving functional capacity, symptom burden, and cardiac remodeling. Landmark trials, including EXPLORER-HCM and MAVERICK-HCM, underscore mavacamten’s ability to reduce LVOT gradients, enhance diastolic function, and lower cardiac biomarkers, heralding a paradigm shift from symptomatic management to disease-modifying therapy. Despite current knowledge gaps in long-term outcomes and diverse population responses, mavacamten establishes a critical foundation for molecularly targeted therapeutics in HCM and broader cardiomyopathies. Full article

Milk fatty acid (FA) synthesis and enteric methanogenesis share common biochemical pathways related to rumen fermentation patterns and microbial volatile FA production. The FA profile of milk is known to correlate with methane (CH₄) emissions; thus, FA profiling has been proposed as an indirect method to predict CH₄ emissions from dairy cattle. This study aimed to (1) investigate the milk FA profiles of Holstein cows to identify candidate biomarkers for predicting CH₄ output (g/d), CH₄ yield (g/kg dry matter intake), and CH₄ intensity (g/kg energy-corrected milk), and (2) develop and compare regression models predicting CH₄ emissions. Forty-eight cows, fed industry standard diets, were enrolled in an exploratory trial. Milk samples and CH₄ measurements were collected thrice per day, and intake was recorded daily. Milk lipids were extracted, transesterified, and subsequently analyzed via gas–liquid chromatography. Three penalized regression models were compared for predicting CH₄ emission metrics using milk FAs and management variables. Methane emission metrics corelated positively with short- and medium-chain FAs, polyunsaturated FAs, and branched-chain FAs, while monounsaturated FAs correlated negatively. Notably, this study observed novel correlations between 11-cyclohexyl-11:0; and 20:3 c5,c8,c11 and CH₄ metrics (|r| = 0.58–0.79). Across all CH₄ metrics, the models demonstrated high predictive accuracy (R² = 0.71–0.87; concordance correlation coefficient = 0.83–0.93). The findings of this study indicate that milk FA profiling may be an effective method to detect CH₄ emissions from cows fed industry standard diets and highlight the need for further refinement of prediction models. Full article

Perfluorooctanoic acid (PFOA), a persistent per- and polyfluoroalkyl substance (PFAS), remains a global toxicological concern due to its ubiquity, bioaccumulation potential, and toxicity even at low concentrations. This study aimed to elucidate the ultrastructural effects of PFOA on the gills of Cyprinus carpio, a species of high ecological and trophic relevance. Gill samples from fish experimentally exposed to two PFOA concentrations (200 ng L⁻¹ and 2 mg L⁻¹), one of which was environmentally relevant, were examined by transmission electron microscopy. The results revealed cytotoxic changes primarily affecting mitochondria-rich (chloride) cells and, to a lesser extent, epithelial and mucous cells. The main alterations included mitochondrial degeneration, Golgi and endoplasmic reticulum stress, and autophagic activation, indicating a coordinated impairment of the endomembrane system. These findings suggest that PFOA induces a bioenergetic and proteo-synthetic imbalance compromising cellular homeostasis. Both direct cytotoxic and indirect endocrine-mediated mechanisms may contribute to the observed lesions. The pronounced sensitivity of mitochondria-rich cells supports their use as generalist biomarkers of PFOA exposure and effect. Within a One Health framework, these cells may also serve as translational models for elucidating conserved subcellular mechanisms of PFAS-induced cytotoxicity across vertebrates, with implications for environmental and human health risk assessment. Full article

Objective: Obesity is characterized by chronic inflammation and gut dysbiosis, yet circulating markers reflecting intestinal immune activation remain limited. Regenerating islet-derived protein 3 alpha (REG3α), an antimicrobial peptide secreted by intestinal Paneth cells, plays a pivotal role in mucosal defense and mirrors microbial–epithelial interactions. In this cross-sectional study, we aimed to examine circulating REG3α levels in infection-free adults with obesity, overweight, and normal weight, and to explore their associations with vitamin D supplementation and biomarkers of inflammation and dysbiosis. Methods: Sixty-nine participants were stratified into control, overweight, and obesity groups. Serum REG3α, interleukin-6 (IL-6), β-defensin-2, high-sensitivity c-reactive protein, ferritin, and presepsin were assessed. Vitamin D status and supplementation history were recorded. Multivariable linear regression, principal component analysis (PCA), and bootstrap mediation models were applied to explore associations and potential indirect effects. Results: REG3α concentrations were higher in overweight and obesity compared to controls (646 ± 217 vs. 521 ± 311 ng/mL); however, the difference was not significant (p = 0.15). Vitamin D supplementation was inversely associated with REG3α (p = 0.06), and this effect appeared weaker in obesity. REG3α correlated positively with IL-6 (ρ = 0.28) and β-defensin-2 (ρ = 0.43). PCA revealed a shared inflammatory–mucosal activation component that predicted REG3α levels. Exploratory mediation suggested a partial indirect effect of vitamin D via reduced inflammatory activity. Conclusions: Circulating REG3α shows associations with indicators of inflammation and vitamin D supplementation in individuals with overweight and obesity. Although differences between groups did not reach statistical significance, the observed trends suggest possible links between mucosal immune activity and metabolic status. These exploratory results warrant validation in larger, longitudinal studies before any biomarker role can be established. Full article