Search Results (706)

Fat deposition in laying hens involves lipid synthesis, transport, storage, and allocation across multiple tissues, yet the metabolic links between abdominal fat (AF) and egg yolk (EY) lipid deposition remain unclear. Here, we integrated whole-genome resequencing data with untargeted metabolomic profiles from the liver, duodenum, ileum, cecum, and serum of 248 purebred Rhode Island Red hens at 100 weeks of age. We estimated metabolite-explained variance (me²) for 22 fat deposition-related traits, evaluated metabolite heritability, and combined Spearman correlation analysis with bidirectional generalized summary-data-based Mendelian randomization (GSMR) to identify shared metabolites and pathways associated with AF and EY traits. The me² showed clear tissue specificity, with the liver, serum, and duodenum showing significant explanatory signals for 77.3% (17/22), 72.7% (16/22), and 68.2% (15/22) of fat-related traits. Liver-, AF-, and body weight-related traits showed stronger metabolomic explanatory signals, with significant proportions of 71.4–100.0%, 28.6–100.0%, and 100.0% across tissues, respectively, whereas EY-related traits showed more restricted and tissue-specific associations (0–33.3%). Correlation analysis identified liver-enriched AF–EY shared metabolites (e.g., NADPH, cholesteryl sulfate, N6,N6,N6-trimethyllysine), most of which showed opposite association patterns between AF- and EY-related traits. Bidirectional GSMR prioritized 20 candidate metabolites with opposite putative effects on AF and EY traits, including CDP-choline, phosphorylcholine, and allantoin. Pathway integration highlighted fructose/mannose metabolism, glycerophospholipid metabolism, ABC transporters, folate/one-carbon metabolism, amino acid metabolism, and energy metabolism as core components of the AF–EY shared network. These findings reveal tissue-specific and shared metabolic bases of fat deposition and identify candidate metabolic signatures associated with lipid partitioning between abdominal fat and egg yolk in laying hens. Full article

Background/Objectives: Vitamin D is a nutrient-related secosteroid system with endocrine, paracrine, immunological, and neurodevelopmental actions relevant to nutritional psychiatry. Psychiatric research has often treated vitamin D either as a cross-sectional correlate of depression or as a non-specific supplement expected to act across heterogeneous diagnostic categories. This narrative review aimed to develop a more discriminating framework in which vitamin D is considered a lifespan neuroimmune and immunometabolic signal whose psychiatric relevance depends on developmental timing, biological context, and phenotype. Methods: Evidence was integrated from developmental epidemiology, neonatal dried-blood-spot studies, randomized trials, meta-analyses, Mendelian randomization studies, clinical guidelines, and mechanistic neuroscience. The review focuses on prenatal and neonatal 25-hydroxyvitamin D, vitamin D-binding protein, free and bioavailable vitamin D, vitamin D receptor signaling, immune and microglial pathways, neurotransmitter systems, neurotrophic signaling, mitochondrial function, oxidative stress, hypothalamic–pituitary–adrenal-axis regulation, and the gut–microbiota–immune–brain axis. Results: The available evidence does not support vitamin D as a universal treatment for psychiatric disorders. Instead, vitamin D deficiency and altered vitamin D biology appear most relevant in biologically and clinically defined risk states, including neurodevelopmental vulnerability, inflammatory depression, psychosis liability, severe mental illness with nutritional deprivation, metabolic comorbidity, and cognitive frailty. Mechanistic data support plausible links with cytokine biology, the tryptophan–kynurenine pathway, dopaminergic and serotonergic systems, stress regulation, and neuroimmune homeostasis. Conclusions: Vitamin D should be conceptualized in psychiatry as a context-dependent neuroimmune and immunometabolic signal rather than a generic psychotropic intervention. Future studies should prioritize biomarker-enriched, developmentally timed, nutrition-centered models of precision prevention and adjunctive care. Full article

Atrophic fracture nonunion is a clinically challenging form of failed bone repair, particularly under inflammatory conditions, but the cell-intrinsic programs that impair the function of skeletal stem/progenitor cells (SSPCs) remain incompletely defined. Here, we integrated public and in-house single-cell RNA sequencing datasets from mouse periosteum, normal fracture healing, and inflammation-associated fracture nonunion models to characterize stromal cell fate changes. Trajectory inference, transcription factor network analysis, and intercellular communication modeling were combined with in vitro and in vivo validation experiments. SSPCs in the nonunion microenvironment were arrested in an undifferentiated state and acquired a pro-inflammatory and pro-ferroptotic phenotype, with enrichment of ferroptosis-related genes including Acsl4. Computational analyses nominated IL-1β as a candidate upstream inflammatory signal, with neutrophils representing a potential source, and linked this signal to NF-κB activation and increased Epas1 activity in SSPCs. In primary SSPCs, IL-1β induced lipid peroxidation, intracellular ferrous iron accumulation, ferroptosis-related protein expression, and impaired osteochondrogenic differentiation. Ferroptosis inhibitor treatment further attenuated IL-1β-induced ferroptosis-related protein changes, supporting pathway specificity. Pharmacological inhibition of EPAS1 with PT2385 attenuated IL-1β-induced ferroptotic stress and restored SSPC differentiation in vitro, while also improving IL-1β-impaired fracture repair in vivo. Mendelian randomization analysis provided additional genetic evidence supporting potential links among IL-1β, EPAS1, and human nonunion risk. Together, these findings suggest that an IL-1β/EPAS1-associated ferroptotic program contributes to SSPC dysfunction during inflammation-associated fracture nonunion and may represent a potential targetable mechanism for improving impaired bone repair. Full article

Nogo (RTN4) proteins and their receptors have emerged as candidate mediators of metabolic regulation and vascular pathology relevant to type 2 diabetes (T2D). The primary objective of this PRISMA-guided systematic review was to evaluate the clinical and cohort evidence for RTN4/RTN4R as potential biomarkers of T2D progression and vascular complications. A secondary objective was to synthesize preclinical mechanistic evidence on the effects of Nogo axis modulation on pathways relevant to the pathogenesis of T2D. We performed a PRISMA-guided systematic review. The protocol was not prospectively registered in PROSPERO. To ensure reproducibility, we provide complete search keywords, the screening log and the full-text exclusion table. PubMed/MEDLINE, EMBASE and Web of Science were searched for studies published 2000–2025; full search keywords are provided in the main text. The search strategy combined and free-text terms with Boolean operators. We included original preclinical and clinical studies, cohort/proteomic analyses, meta-analyses, and mechanistic papers reporting expression, function, signaling, or clinical associations of Nogo proteins/receptors in metabolic or vascular outcomes. Exclusion criteria: non-English articles, unclear methods, studies outside 2000–2025, and studies lacking primary data. Two reviewers independently screened records; conflicts were resolved by consensus. Study quality was appraised using established tools (SYRCLE for animal studies, Newcastle–Ottawa Scale for cohort/case-control studies). Preclinical evidence supports tissue-specific roles for RTN4 isoforms and receptors in the regulation of insulin secretion, proGCG → GLP-1 processing, ER homeostasis, and vascular permeability through the Src/PI3K/Akt and RhoA/ROCK axes. Cohort and proteomic analyses report associations between RTN4/RTN4R or serum NogoB and faster progression of T2D or vascular complications, but genetic assessment of causality (Mendelian randomization) has so far provided limited support in available data sets. Findings are heterogeneous with respect to directionality and tissue localization. RTN4 signaling exhibits tissue-specific mechanisms relevant to glucose regulation and vascular biology and warrants further translational study. However, heterogeneity across studies and limited genetic support for causality indicate that isoform-specific quantitative validation, longitudinal cohorts and integrated genetic–functional analyses are required before RTN4/RTN4R can be considered as clinical biomarkers. Full article

Epilepsy is a heritable neurological disorder that is frequently comorbid with sleeping difficulties, including short/long sleep duration and insomnia. Although epidemiological studies have consistently reported the comorbidity between sleep disturbances and epilepsy, the shared genetic architecture and molecular mechanisms underlying this relationship remain poorly characterized, hindering therapeutic development. In this study, we integrated large-scale genome-wide association study (GWAS) summary statistics of European ancestry to dissect the genetic and molecular links between sleep traits and epilepsy. Using LDSC and GWAS-pw, we identified modest but statistically significant (Bonferroni-corrected) global and local genetic correlations between sleep behaviors and epilepsy. Subsequent CPASSOC cross-trait meta-analysis and transcriptome-wide association studies (TWAS) pinpointed specific pleiotropic loci and shared candidate genes, including SPAG7, VRK2, and LINC00925, which are functionally associated with neuroimmune signaling. While preliminary Phenome-Wide Association Study (PheWAS) profiling of these candidate targets did not identify major adverse associations in current databases, we emphasize that rigorous in vitro and in vivo experimental validations are required before considering them for therapeutic strategies. Finally, pleiotropy-robust bidirectional Mendelian Randomization (MR) analyses suggested unidirectional causal liability from epilepsy to short sleep duration. Although the estimated causal effect size was minimal, it reflects lifelong polygenic architecture rather than acute clinical magnitude. In conclusion, our multi-omics approach unveils the shared genetic architecture of the sleep-epilepsy axis and highlights potential biomarkers for future functional investigation. Full article

Ovarian cancer (OC) comprises multiple histotypes with distinct mechanisms, molecular features, and clinical behavior. We used Mendelian randomization (MR) to map histotype-stratified metabolic pathways and connect them to drug targets, establishing a translatable target–metabolic node–histotype risk chain. We built a multi-stage MR framework using Integrative Epidemiology Unit (IEU) OpenGWAS summary statistics. After screening 1400 plasma metabolites against overall ovarian cancer in UK Biobank and Ovarian Cancer Association Consortium (OCAC) with KEGG enrichment, we traced a prespecified amino acid/energy–nitrogen axis using histotype-stratified univariable MR and pathway-restricted multivariable MR. We then performed cis drug-target MR for PPARG, DPP4, ABCC8/KCNJ11, and SLC5A2, integrated triangulation, colocalization, and mediation analyses, and experimentally interrogated the prioritized PPARG/ABCC8-KCNJ11–lactate–invasive mucinous ovarian cancer (IMOC) triangle. Screening nominated 55 and 72 metabolites in UK Biobank and OCAC, respectively (IVW p < 0.05), highlighting amino-acid nitrogen and central-carbon metabolism. Univariable Mendelian randomization (UVMR) showed marked heterogeneity: alanine increased low-grade serous ovarian cancer (LGSOC) risk, glutamate was protective for endometrioid OC, and lactate-related traits most consistently implicated the low-grade/borderline serous lineage. In multivariable Mendelian randomization (MVMR), tryptophan and lactate levels emerged as independent risk nodes for serous low-grade plus low malignant potential (LG + LMP). Drug-target MR prioritized PPARG as protective (OR = 0.18) and ABCC8/KCNJ11 as risk-increasing (OR = 7.50) for IMOC, with opposite target → lactate effects supporting a directionally symmetric target–lactate–IMOC triangle. Experimental perturbation in mucinous ovarian cancer models produced concordant reciprocal changes in lactate and malignant phenotypes, extending this triangle biologically. This integrative MR framework delineates histotype-specific metabolic drivers and links them to actionable targets, providing a roadmap from genetic prioritization to mechanistic and translational validation. Full article

Emerging research highlights the complex interplay between the gut microbiome, skin health, and environmental exposures, forming what is now recognized as the gut–skin–exposome axis. This narrative review explores the role of gut microbiome dysbiosis—a disruption in the balance of intestinal microorganisms—in the pathogenesis and progression of various non-communicable inflammatory skin diseases, including acne, atopic dermatitis, psoriasis, rosacea, systemic lupus erythematosus, chronic spontaneous urticaria, hidradenitis suppurativa, and alopecia areata. This review synthesizes mechanistic studies, clinical trials, and Mendelian randomization data to elucidate how altered gut microbial composition contributes to systemic and cutaneous inflammation. Key modifiable factors, such as diet, antibiotics, stress, and sleep, as well as interventions like probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, are discussed for their potential therapeutic value. By integrating clinical insights with microbiome science, this review underscores the importance of a holistic, systems-based approach in managing inflammatory skin diseases, offering clinicians evidence-based strategies to improve patient outcomes through gut microbiome modulation. Full article

Objective: To elucidate the role of cytoskeleton-associated protein 2 (CKAP2) in gastric cancer (GC) progression and evaluate its prognostic and potential protective significance. Methods: The candidate genes for GC were identified using differential expression and weighted gene co-expression network analysis (WGCNA). A panel of machine learning algorithms was applied for obtaining the key genes and yielding the hub target gene CKAP2 through protein–protein interaction (PPI) networks and single-cell RNA sequencing analysis. Further, the functional role of CKAP2 was explored through single-cell virtual knockout and pathway enrichment analysis. Meanwhile, the survival analysis and Mendelian randomization (MR) were used to evaluate the clinical relevance and causality of CKAP2. Finally, the expression of CKAP2 was further validated in clinical tissues and GC cell lines through Western blot. Results: A total of 20 candidate genes were identified, of which 8 were identified as hub genes through machine learning. Integrative PPI and single-cell analyses ultimately identified CKAP2 as the key gene. Virtual knockout analysis showed that the related differentially expressed genes were significantly enriched in the 5-HT pathway. Survival analysis demonstrated that elevated CKAP2 expression was associated with improved prognosis. MR analysis further suggested that CKAP2 might act as a protective factor, while 5-HT was associated with an increased risk of GC. Experimental validation confirmed that CKAP2 is significantly upregulated in GC tissues and cell lines. Conclusions: CKAP2 is a potential prognostic biomarker and protective factor in GC, possibly exerting its effects through regulation of the 5-HT pathway. These findings provide new insights into the mechanisms and potential therapeutic targets of GC. Full article

Background/Objectives: Observational studies have reported comorbidity between diabetic retinopathy (DR) and physical frailty, but their genetic interplay remains incompletely understood. This study evaluated shared genetic architecture and potential causal relationships between DR severity and frailty-related phenotypes (FRPs). Methods: GWAS summary statistics were analyzed for four DR phenotypes (broad DR, background DR [BDR], severe non-proliferative DR, and proliferative DR [PDR]) and six FRPs, including frailty index (FI), appendicular lean mass, handgrip strength (HGS), and walking pace (UWP). Global and local genetic correlations were estimated using LDSC, HDL, and LAVA. Causality was assessed using bidirectional Mendelian randomization (MR) and latent causal variable (LCV) analyses. Biological mechanisms were investigated using partitioned heritability, cross-trait meta-analysis, Bayesian colocalization, tissue and cell enrichment, prioritization (MAGMA/TWAS), and 3D chromatin annotation. Results: BDR and PDR showed positive genetic correlations with FI and negative correlations with UWP. Local genetic correlation analyses identified 82 significant regions, including signals on chromosome 6. MR supported a directional effect in which genetic liability to DR was associated with higher FI and lower HGS, with no evidence of reverse causation. LCV indicated partial genetic causality within a shared polygenic architecture. Cross-trait meta-analysis and colocalization highlighted the MHC region, prioritizing C2, AIF1, NOTCH4, and EHMT2. Additional non-MHC loci included the BCL2L15 gene cluster and TERF1. Conclusions: DR and frailty share genetic determinants involving neurovascular, metabolic, and immune-inflammatory pathways, supporting an association between DR liability and frailty-related decline. Future longitudinal and functional studies are needed to validate these findings and assess candidate pleiotropic genes. Full article

Background/Objectives: Immune-inflammatory activation is a central feature of aneurysmal subarachnoid hemorrhage (aSAH), yet the epitranscriptomic mechanisms underlying this response remain insufficiently understood. This study aimed to investigate RNA methylation-associated immune dysregulation in aSAH and to identify potential biomarkers and signaling pathways. Methods: Four Gene Expression Omnibus datasets were analyzed to characterize RNA methylation regulator-related immune alterations in aSAH. Single-sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA), and intersection with ImmPort immune genes were used to identify candidate genes. A total of 159 machine learning combinations were evaluated for model construction and external validation. Two-sample Mendelian randomization, single-cell RNA sequencing (scRNA-seq), and CellChat analyses were further performed. Peripheral blood samples from patients with aSAH (n = 12) and matched healthy controls (n = 12) were used for total m6A quantification and quantitative real-time PCR (qRT-PCR) validation, while Western blotting and immunofluorescence were used to validate the protein expression of LIFR, GP130, IGF2BP2, and RBM15B. Results: Eleven RNA methylation regulators were differentially expressed between aSAH and controls in GSE122897. The WGCNA module most strongly associated with RNA methylation regulator-related scores was enriched in immune response and myeloid activation pathways. Intersection analysis identified 25 candidate immune-inflammatory genes associated with RNA methylation regulator-related transcriptional patterns. Among 159 algorithms, an XGBoost-LASSO pipeline selected oncostatin M (OSM) as the key variable, and the resulting RNA methylation regulator-related immune-derived gene signature (RMRIGS) showed good discrimination between aSAH and controls across training and validation cohorts. Mendelian randomization supported a protective association of genetically predicted OSM expression with subarachnoid hemorrhage risk (IVW OR = 0.66, p = 0.014). Single-cell analysis showed that Osm was predominantly enriched in infiltrating Ccr2+ macrophages, whereas Lifr and Il6st were broadly expressed in activated microglial subpopulations, indicating the presence of an Osm − (Lifr + Il6st) communication axis after SAH. Clinically, total m6A levels were increased in peripheral blood samples from patients with aSAH, and OSM, together with several RNA methylation regulators, was upregulated and associated with m6A-related changes. In experimental models, the protein expression levels of LIFR, GP130, IGF2BP2, and RBM15B were all increased after SAH-related stimulation. Conclusions: RNA methylation programs may be involved in immune dysregulation in aSAH. The OSM-centered RMRIGS was associated with disease status and may provide insight into the interaction between peripheral immune activation and post-SAH neuroinflammation. The potential involvement of the OSM–LIFR/GP130 signaling axis and its association with RNA methylation regulator-related alterations warrant further investigation. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disorder driven by genetic predisposition, epigenetic programming, metabolic rewiring, and immune dysregulation. Although population genetics and single-cell transcriptomics have advanced our understanding, the multi-omic causal architecture of MASLD at cellular resolution remains poorly defined. This study aimed to establish an integrative framework linking genetic causality to cell-type-specific tissue dysfunction. Methods: Multi-layered Mendelian randomization (MR) and summary-data-based MR (SMR) across large-scale eQTL and pQTL datasets were applied to prioritize causal genes. Single-cell eQTL-based MR across 14 immune lineages generated cell-type-specific causal hypotheses, which were validated using human hepatic single-cell RNA-sequencing data (GSE136103). Two-step mediation MR quantified upstream epigenetic and downstream metabolic mechanisms. A high-fat diet (HFD)-induced murine model provided organismal validation. Results: Multi-layered MR nominated PLXND1 as a robust causal driver of MASLD. Single-cell eQTL-based MR revealed a functional dichotomy: PLXND1 upregulation in CD8⁺ effector memory T-cells decreased MASLD risk (OR = 0.486, 95% CI: 0.290–0.813, p = 0.006), whereas upregulation in natural killer cells (OR = 1.567, 95% CI: 1.337–1.837, p < 0.001), non-classical monocytes, and dendritic cells increased risk. Human hepatic single-cell transcriptomics confirmed that PLXND1 marks an anti-fibrotic, IFNG-high CD8⁺ T subset and a pro-inflammatory lipid-associated macrophage (LAM) population. Mediation MR identified DNA methylation at cg26767922 and cg08471739 as protective mediators acting predominantly via PLXND1 downregulation (92.39% and 64.50% mediation, respectively), and linked PLXND1 to six circulating metabolites. HFD mice showed significant hepatic PLXND1 upregulation. Conclusions:PLXND1 functions as a lineage-dependent molecular switch in MASLD, validated across genetic, epigenetic, metabolic, and single-cell dimensions. These findings caution against systemic PLXND1 blockade and support precision therapeutic strategies targeting hepatic innate immune cells. Full article

Osteoporosis (OP) and osteoarthritis (OA) frequently coexist in the elderly, yet shared molecular pathways remain unclear. We employed weighted gene co-expression network analysis (WGCNA), independent cohort differential verification, and integration of multiple datasets to explore the association between the two diseases and identify the hub genes. Then, through Mendelian randomization and single-cell sequencing methods, we confirmed that SON might be the key protein linking these two diseases and a promising therapeutic target for comorbidity. Additionally, this study utilized the FDA drug database for virtual screening to evaluate the potential of SON protein as a drug target. Nilotinib, with a high docking score, was listed as a candidate drug. Overall, our findings suggest that SON may play a protective role in the comorbidity of OP and OA, but further functional studies are required to confirm its causal role. Moreover, Nilotinib shows inhibitory effects on osteoclast differentiation and targets SON in vitro, indicating its potential as a candidate drug for further investigation. Full article

Telomere length (TL) is a key determinant of cellular aging and genomic stability, influenced by genetic, molecular, and environmental factors. Progressive telomere shortening has been associated with degenerative and cardiovascular diseases, whereas longer telomeres have been linked to an increased risk of cancer, highlighting a dual and context-dependent relationship between TL and disease susceptibility. Evidence from genome-wide association studies (GWAS) and Mendelian randomization analyses indicates that TL is a highly heritable and polygenic trait, regulated by variants in genes such as TERT, TERC, RTEL1, and POT1, as well as components of the shelterin and CST complexes. This study integrates genetic variants associated with telomere shortening and elongation, including their functional classification, proposed molecular mechanisms, and ACMG/AMP categorization, together with global and Latin American allele frequency data. These variants may participate in key processes such as telomerase activity, telomerase RNA stability, and telomere replication, thereby influencing susceptibility to multiple diseases. However, current evidence is largely derived from European and Asian populations. Given the highly admixed nature of Latin American populations, population-specific studies are required to identify unique genetic determinants and to improve the application of precision medicine. Full article

Background/Objectives: Hyperuricemia is a metabolic disorder characterized by renal dysfunction and systemic inflammation. While Clematis chinensis Osbeck is traditionally used for gout-related conditions, its chemical basis and precise mechanisms remain poorly understood. This study aimed to characterize the bioactive fraction (CWE-60EF) and elucidate its multi-target regulatory mechanisms against hyperuricemia. Methods: Qualitative and quantitative chemical profiling of CWE-60EF was performed using high-resolution LC-MS/MS. Its anti-hyperuricemic activity was validated using in vitro xanthine oxidase (XOD) inhibition, a zebrafish model, and HK-2 cell injury models. Mechanisms were explored through an integrated approach combining bioinformatics, Mendelian randomization (MR), and molecular docking. Results: A total of 50 compounds, primarily alkaloids and flavonoids (e.g., magnoflorine and phloretin), were characterized in CWE-60EF, and major marker compounds were quantitatively standardized. The fraction significantly inhibited XOD activity and rescued hyperuricemia-associated phenotypes in zebrafish. In HK-2 cells, CWE-60EF suppressed adenosine- and urate-induced cellular injury and the transcriptional expression of pro-inflammatory cytokines (IL-6 and IL-1β). MR analysis provided genetic evidence supporting IL-6 as a causal mediator of gout risk. Integrative analysis revealed that the protective effects of CWE-60EF are mediated through the coordinated regulation of purine metabolism, inflammatory cascades, and urate transporters (URAT1/GLUT9). Conclusions: This study demonstrates that CWE-60EF is a quantitatively standardized bioactive fraction that exerts anti-hyperuricemic, renoprotective, and anti-inflammatory effects by modulating uric acid metabolism and inflammation. By integrating genetic causality with phytochemical validation, our findings provide a novel mechanistic foundation for the traditional application of C. chinensis in hyperuricemic disorders. Full article

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global public health crisis, progressing to hepatic cirrhosis and hepatocellular carcinoma. This study investigated the causal role of systemic iron status in MASLD progression. Methods: A two-sample Mendelian randomization (MR) design was implemented, with genetic variants serving as instrumental variables for four core systemic iron biomarkers. Outcome data for hepatic steatosis (8785 cases; 912,105 controls) and hepatic fibrosis/cirrhosis (3798 cases; 904,599 controls) were extracted from the FinnGen and UK Biobank databases. Multiple complementary MR methodologies and three instrumental variable selection strategies were applied to ensure robust causal inference. Results: Genetically predicted higher serum iron (odds ratio, OR: 1.42, 95% confidence interval, 95% CI: 1.34, 1.50), ferritin (OR: 1.84, 95% CI: 1.55, 2.18), and transferrin saturation (TfSat, OR: 1.24, 95% CI: 1.19, 1.30), together with lower total iron-binding capacity (TIBC, OR: 0.81, 95% CI: 0.77, 0.85), were significantly associated with increased hepatic steatosis risk (p < 0.00625). Similar associations were observed for hepatic fibrosis/cirrhosis: serum iron (OR: 1.66, 95% CI: 1.29, 2.14), ferritin (OR: 2.52, 95% CI: 1.52, 4.18), TfSat (OR: 1.40, 95% CI: 1.19, 1.63), and reduced TIBC (OR: 0.70, 95% CI: 0.60, 0.81). MR-Bayesian model averaging prioritized serum iron (MIP: 0.85, ${\widehat{\theta }}_{\mathrm{MACE}}$: 0.295; PP: 0.725; ${\widehat{\theta }}_{\mathsf{\lambda }}$: 0.344) as the top-ranked factors for steatosis and TIBC (MIP: 0.604, ${\widehat{\theta }}_{\mathrm{MACE}}$: −0.240; PP: 0.476, ${\widehat{\theta }}_{\mathsf{\lambda }}$: −0.358) for fibrosis/cirrhosis. Conclusions: Elevated systemic iron status causally drives MASLD onset and progression, highlighting iron homeostasis and ferroptosis as potential targets for prevention and clinical management. Full article