Search Results (264)

Computer-assisted sperm analysis was conducted to phenotypically and genetically assess the sperm motility traits of Jinding drakes. The phenotypic evaluation revealed moderate variability across motility parameters, consistent with a polygenic inheritance pattern. Correlation analysis further demonstrated strong associations among velocity-related traits and inverse relationships between linearity and lateral head displacement metrics. Genome-wide association studies identified 15 significant single-nucleotide polymorphisms (SNPs) associated with five key sperm motility traits (straight-line velocity, curvilinear velocity, average path velocity, amplitude of lateral head displacement, and mean angular displacement) at a genome-wide threshold of p < 1 × 10⁻⁶. Notably, of these 15 SNPs, nine were concentrated on chromosome 1, indicating the presence of a genomic hotspot for regulation of sperm motility. Pleiotropic effects were evident, as several SNPs were found to influence multiple motility traits. Candidate genes implicated in essential sperm functions included Myo16 (cytoskeletal dynamics), Cep76 (flagellar structure), and Jarid2 (epigenetic regulation during spermatogenesis), as well as genes involved in membrane integrity, mitochondrial function, and immune regulation. These findings provide novel insights into the genetic architecture underlying sperm motility of Jinding drakes and establish a basis for molecular breeding strategies to enhance reproductive efficiency of waterfowl. 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

Argonaute (AGO) proteins are central components of RNA silencing. While OsAGO18 is a known defense factor in antiviral immunity, its involvement in basal development and its transcriptomic behavior during fungal stress remains to be fully elucidated. In this study, based on its specific dual-localization in chloroplasts and processing bodies (P-bodies), we investigated the pleiotropic effects of OsAGO18 through transcriptomic network analysis of rice responding to the blast fungus Magnaporthe oryzae B.C. Couch. Our analysis revealed that the OsAGO18-mediated co-expression network is highly correlated with ribosome biogenesis and cell wall organization. Notably, the analyzed datasets reveal that this growth-related network is significantly suppressed upon M. oryzae challenge, highlighting a transcriptomic shift in OsAGO18 during the growth-to-defense transition. Phenotypic evaluations demonstrated that OsAGO18 overexpression accelerates early seedling growth and primary root elongation by promoting endogenous indole-3-acetic acid (IAA) accumulation, whereas ago18 mutants maintain basal growth rates without significant IAA fluctuations, reflecting robust genetic compensation within the highly redundant AGO family. Mechanistically, our integrated analysis suggests that OsAGO18 acts as a putative molecular decoy to sequester miR396d, thereby relieving the repression of the Growth-Regulating Factor OsGRF6 and triggering downstream auxin-dependent cascades. Collectively, our findings highlight OsAGO18 as a pivotal regulator of early seedling development and characterize its transcriptomic responsiveness to biotic stress, providing a plausible molecular link between post-transcriptional RNA regulation and rice growth coordination. Full article

Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer progression, cellular senescence, and age-associated immune dysregulation. A central argument of this review is that PAI-1 should be understood not only as a downstream biomarker of aging-associated pathology, but also as an active effector linking senescence-associated secretory phenotype (SASP) signaling, chronic low-grade inflammation, impaired immune surveillance, fibrotic extracellular matrix remodeling, and a prothrombotic state. In this framework, PAI-1 may function as an immune-aging checkpoint: a molecular node through which senescent, stromal, malignant, and inflammatory cells reinforce immune evasion and tissue dysfunction. Structure-guided drug discovery has enabled the development of small-molecule PAI-1 inhibitors, including TM5275, TM5441, TM5509, and TM5614. Among these, TM5614 is an orally available investigational compound that has progressed to clinical evaluation. Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia. This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds. Full article

Background/Objectives: Radon exposure has recently been associated with asthma morbidity, including increased airway inflammation and school absenteeism in children, though limited data on underlying biological mechanisms exist. Interleukin-6 (IL-6), a pleiotropic cytokine implicated in both Type 2-low airway inflammation and radon-related lung carcinogenesis, may represent a key mechanistic link between radon exposure and asthma morbidity. We aimed to evaluate the association between indoor radon exposure and plasma IL-6 levels in children with asthma and whether this relationship differs by allergic sensitization status. Methods: We analyzed baseline data from the School Inner-City Asthma Study, a prospective cohort of children aged 4–13 years with persistent asthma. Monthly indoor radon concentrations at each participant’s residential ZIP Code Tabulation Area were estimated using a validated spatiotemporal prediction model. Plasma IL-6 was measured from baseline blood samples. Multivariable linear mixed-effects models with random intercepts for school were used to assess the association between radon exposure and IL-6, adjusting for demographic, clinical, and socioeconomic covariates. Effect modification by allergic sensitization was evaluated using an interaction term. Results: Among 144 participants, 62.5% were allergen-sensitized. The median home radon concentration was 46.6 Bq/m³ (range 30.7–99.9), and the mean plasma IL-6 was 0.22 pg/mL (SD 0.41). A significant interaction was observed between radon exposure and allergic sensitization status (β-interaction = −0.012; p = 0.014), indicating differential effects by phenotype. Among non-sensitized children, higher radon exposure was associated with increased IL-6 levels (β = 0.0088; p = 0.044), corresponding to a 0.32 pg/mL rise in IL-6 per 37 Bq/m³ increase in radon. No significant association was observed among sensitized children. Conclusions: Indoor radon exposure is associated with higher plasma IL-6 levels in non-sensitized children with asthma, suggesting a potential IL-6–mediated pathway linking radon exposure to asthma morbidity in the Type 2-low phenotype. These findings highlight heterogeneity in environmental asthma responses and support further investigation into radon mitigation as a modifiable factor to improve asthma outcomes. IL-6 may serve as a biomarker to identify children most susceptible to radon-related airway inflammation, guiding personalized mitigation strategies and targeted interventions to improve asthma outcomes. Future studies should incorporate direct home radon measurements, comprehensive endotyping panels, and longitudinal biomarker sampling to validate these findings and elucidate whether IL-6 trans-signaling pathways mediate radon-induced airway injury in non-allergic asthma. Full article

Cultivated strawberry (Fragaria × ananassa) is an allo-octoploid for which the genetic basis of fruit appearance traits has not been comprehensively elucidated. This study investigated the genetic architecture of fruit color and morphological traits using integrated digital phenotyping and genome-wide association analysis of a core collection of diverse strawberry germplasm maintained for Korean breeding programs. A 108-accession core collection was assembled, genotyped, and phenotyped for 12 fruit quality traits. Population structure analysis identified K = 10 genetic clusters, and a Mantel test confirmed significant genotype–phenotype correspondence (r = 0.38, p < 0.001). Genome-wide association studies (GWAS) using BLINK and MLMM identified 15 significant marker–trait associations across six traits. Pleiotropic loci on chromosomes 15 (4C) and 22 (6B) were consistently associated with fruit lightness (L*) and red channel intensity (R) in both models, and the 6B locus explained approximately 18% of the phenotypic variance for each trait. Gene Ontology enrichment implicated transcriptional regulation, SUMOylation, and plastid-to-chromoplast transition, suggesting that the identified loci influenced fruit coloration through cellular regulatory mechanisms rather than direct pigment biosynthesis. These findings provide a genomic foundation for dual-trait marker-assisted selection targeting light and vividly red fruits for strawberry breeding. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks such as amyloid-β plaques and neurofibrillary tangles. In recent years, chronic neuroinflammation has emerged as a central mechanism linking genetic, metabolic, and immune dysfunctions in AD. Activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species that exacerbate synaptic and neuronal injury, while impaired clearance mechanisms and blood–brain barrier disruption further sustain inflammation. A growing body of research highlights the role of immunometabolism—the bidirectional interaction between immune activation and cellular metabolism—in shaping glial phenotypes and disease progression. Dysregulation of glucose, lipid, and amino acid metabolism, together with alterations in key metabolites such as lactate, NAD⁺, and reactive oxygen species, promotes a maladaptive inflammatory state. Genetic factors including APOE4 and TREM2 variants affect microglial lipid handling pathways, while systemic metabolic disorders and gut microbiota alterations amplify neuroinflammatory cascades. Natural bioactive compounds, particularly polyphenols, have gained attention for their ability to modulate immunometabolic pathways. By activating AMPK and SIRT1 and inhibiting mTOR and NLRP3 inflammasome signaling, polyphenols may tune mitochondrial function, redox homeostasis, and autophagy, promoting adaptation to chronic metabolic stress. Therefore, metabolic-immune interactions represent pleiotropic therapeutic avenues for AD. Understanding how immunometabolites and nutrient-sensing pathways regulate compartmentalized inflammation in the CNS may pave the way for novel interventions that combine metabolic precision with neuroprotective efficacy. Full article

Muco-obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis, are characterized by the accumulation of highly viscoelastic mucus that compromises mucociliary clearance and fosters infection and inflammation. Mucoactive therapy, encompassing both true mucolytics and non-cleaving agents, seeks to restore airway patency by altering mucus structure, hydration, and transport properties, yet its clinical impact remains variable. This narrative review provides a critical reappraisal of the pharmacological actions and therapeutic outcomes of the main mucolytic agents: N-acetylcysteine (NAC), erdosteine, carbocisteine, bromhexine, ambroxol, and dornase alfa. Beyond their classical role in reducing mucus viscosity, these drugs exhibit pleiotropic effects, including antioxidant, anti-inflammatory, and immunomodulatory activities. Specifically, for thiol-based compounds, the action consists of breaking the disulfide bonds that stabilize the mucin network; for carbocisteine, it lies in modulating mucin glycosylation and chloride transport. Ambroxol and bromhexine act by stimulating surfactant secretion and enhancing mucociliary clearance. Finally, dornase alfa exerts an enzymatic effect on extracellular DNA, a key contributor to the tenacity of mucus in cystic fibrosis. Clinical evidence indicates that NAC and erdosteine can reduce exacerbation rates in COPD, carbocisteine shows benefit with prolonged administration, and dornase alfa remains a cornerstone in CF management. However, therapeutic efficacy is constrained by heterogeneous mucus composition, pharmacokinetic limitations, and disease-specific variability. A key interpretative message is that clinical benefit appears greatest when the dominant biophysical determinant of mucus pathology is specifically targeted, supporting a transition from broad disease-label prescribing to mechanism-informed, phenotype-aware mucolytic therapy. Emerging strategies, such as agents targeting mucin–DNA interactions and advanced inhalation delivery systems, promise improved specificity and durability. By integrating mechanistic insights with clinical data, this review underscores the need for personalized mucolytic therapy and innovative approaches to overcome current challenges in managing muco-obstructive lung diseases. Full article

Aging and obesity accompanied with hormonal disequilibrium represent critical, inter-related risk factors for breast cancer, significantly influencing disease incidence, progression, and therapeutic outcomes. This review aims to elucidate the multifaceted biological mechanisms linking obesity and aging to breast carcinogenesis, with a particular focus on the emerging therapeutic and preventive potential of postbiotics as molecules targeting cellular events important for cancer growth and responsiveness. Despite continuous advancement, breast cancer therapy still poses several challenges, such as treatment-induced acquired resistance, which is boosted by the inflammatory phenotype of senescent cancerous cells, as well as undesired side effects resulting from the destruction of normal cells. Such a complex background of breast carcinogenesis and oncotherapy resistance opens avenues to search for new preventive approaches and adjunctive treatment regimens. Postbiotics demonstrate a variety of benefits due to their selective antineoplastic activity, as well as the cytoprotective potential associated with antioxidant, anti-inflammatory and anti-senescent properties. Pleiotropic effects of postbiotics make them a promising tool for counteracting cellular and physiological disturbances that favor breast cancer development, including age- and obesity-related factors. They are prospective adjunctive agents in oncotherapy, albeit their efficacy and safety need to be thoroughly evaluated in clinical studies prior to implementation in routine treatment modes. Full article

Endocrine disorders are increasingly recognized as major contributors to secondary cardiomyopathies, leading to profound alterations in cardiac structure and function. This comprehensive review synthesizes current evidence on the genetic basis of cardiomyopathies associated with endocrine conditions, including primary aldosteronism, Cushing’s syndrome, pheochromocytoma/paraganglioma, acromegaly, thyroid disorders, hyperparathyroidism, and diabetic cardiomyopathy. We examine the contribution of somatic and germline mutations, genetic polymorphisms, shared molecular pathways transforming growth factor-β (TGF-β)/SMAD (TGF-β/SMAD signaling, the renin–angiotensin–aldosterone system, oxidative stress, and calcium handling), sarcomeric gene modifiers, ion channel variants, and epigenetic mechanisms to disease pathogenesis. We propose a conceptual framework distinguishing three major categories of genetic involvement: (i) variants causing the primary endocrinopathy; (ii) genetic modifiers of myocardial susceptibility under conditions of hormonal excess; and (iii) direct pleiotropic effects, whereby single gene variants independently cause both endocrine and cardiac phenotypes. In addition, we discuss genotype–phenotype correlations, ethnic and population differences in genetic susceptibility, the emerging role of polygenic risk scores, and precision medicine approaches. Overall, this review provides an integrated perspective on the complex genetic architecture of endocrine-related cardiomyopathies and outlines practical considerations for genetic testing aimed at improving patient management and clinical outcomes. Full article

Background: Improving grain yield in wheat remains a top priority, requiring integrated breeding and genetic strategies. This complexity poses a major challenge, driven by quantitative polygenic inheritance, environmental influence, and intricate genetic interactions. We investigated genetic factors and their interactions for agronomic and yield traits in two high-yielding winter wheat cultivars adapted to the US Southern Great Plains. Methods: A bi-parental mapping population consisting of 221 F₇ recombinant inbred lines (RIL) derived from ‘TAM 204’ and ‘Iba’ was evaluated for three years in 11 Texas environments. Both parents and RIL population were genotyped on Illumina NovaSeq 6000 and sequences were aligned to IWGSC RefSeq v1.0 using Bowtie2 for SNP calling. For QTL analyses, each trait was analyzed by individual environment, across multiple environments and mega-environments. Results: A total of 86 QTL were mapped for five traits and among them 32 were consistent in more than one environment or analysis. Among consistent QTL, four were pleiotropic to more than one agronomic or yield traits mapped on chromosomes 2B (57.18, 59.47 Mb) and 2D (29.34, 40.64 Mb). The consistent QTL on chromosome 2D (29.34 Mb) was pleiotropic to GYLD, DTH, TW, TKW and explained maximum phenotypic variation for all traits, representing photoperiod gene (Ppd-D1). Another QTL on chromosome 2D (40.64 Mb) was pleiotropic to GYLD and TW and based on the physical position comparisons it likely reflects a unique locus in Iba. The pleiotropic consistent QTL Qgyld.tamu.2B.59 from TAM 204 represents Ppd-B1 gene. Moreover, it is more likely that Qdth.tamu.5B.575 represents the Vrn-B1 gene in Iba. A total of 23 digenic epistatic interactions involved consistent QTL for all traits. Amongst these, epistatic interactions between the consistent QTL on 2B (57.18 Mb) and 2D (29.34 Mb) were observed for GYLD, DTH and TKW. Conclusions: Our findings revealed key allelic diversity and interaction effects in elite wheat cultivars, paving the way for marker development for identified pleiotropic loci and implementation in marker-assisted selection and recombination breeding. Full article

Background/Objectives: Retinoblastoma represents the most common intraocular malignancy in childhood; however, the clinical applicability of mitomycin C (MMC) is restricted by dose-dependent ocular toxicity. Consequently, the development of pharmacological strategies that sensitize tumor cells to MMC while allowing dose reduction remains an unmet therapeutic objective. In this context, quercetin, a bioactive flavonoid with pleiotropic anticancer properties, has emerged as a potential chemosensitizing agent. Methods: Human retinoblastoma cell lines Y79 and WERI-Rb1 were exposed to MMC and quercetin, administered either individually or in fixed-ratio combinations. Cytotoxic responses were quantified through dose–response modeling and IC₅₀ determination following 24 and 48 h of treatment. Drug–drug interactions were quantitatively characterized using the Chou–Talalay combination index (CI) approach and isobologram analysis. Cell cycle distribution was assessed by propidium iodide (PI)-based flow cytometric analysis to evaluate treatment-associated alterations in cell cycle progression. Apoptotic cell death was assessed by Annexin V-FITC/PI flow cytometry, while transcriptional modulation of genes associated with apoptosis, cell cycle regulation, and oxidative stress (BAX, BCL-2, TP53, CASP3, CDKN1A, and HMOX1) was evaluated by qRT-PCR. Modulation of tumor-supportive signaling was examined by measuring VEGF and IL-6 secretion. Translational relevance was further investigated using a three-dimensional (3D) tumor spheroid model, and the functional contribution of reactive oxygen species (ROS) was interrogated through N-acetyl-L-cysteine (NAC) rescue experiments. Results: Quercetin significantly enhanced the cytotoxic activity of MMC in both retinoblastoma cell lines, with CI values below 1 across IC₅₀–IC₉₀ effect levels, indicating a synergistic pharmacological interaction. PI–FACS analysis revealed that combined MMC and quercetin treatment induced a pronounced accumulation of cells in the G2/M phase, consistent with cell cycle arrest, with a more marked effect observed in Y79 cells compared with WERI-Rb1 cells. Combination treatment resulted in a pronounced increase in apoptotic cell populations compared with single-agent exposure and triggered a coordinated pro-apoptotic transcriptional response, characterized by increased expression of BAX, TP53, CASP3, CDKN1A, and HMOX1, alongside suppression of BCL-2 and a marked shift in the BAX/BCL-2 ratio. Concurrently, VEGF and IL-6 secretion were significantly reduced, reflecting attenuation of pro-angiogenic and pro-inflammatory signaling. Notably, synergistic cytotoxicity was maintained in 3D tumor spheroids, where combined treatment induced spheroid shrinkage, architectural disruption, and reduced viability. NAC pretreatment diminished ROS accumulation and partially restored cell viability, indicating that oxidative stress contributes to, but does not solely account for, the observed synergistic cytotoxic effect. Conclusions: Collectively, these findings indicate that quercetin appears to function as an effective chemosensitizing adjuvant to MMC in retinoblastoma models, through transcriptional changes consistent with p53-associated apoptotic signaling at the transcriptional level, G2/M cell cycle arrest, and partial involvement of ROS-related cellular stress responses, along with suppression of tumor-supportive signaling pathways. The preservation of synergistic activity in 3D tumor spheroids supports the potential preclinical relevance of this combination. However, these findings are based on transcriptional and phenotypic analyses and should be interpreted as hypothesis-generating, requiring further validation through protein-level and in vivo studies before translational application. Full article

Heart failure (HF) is a systemic syndrome in which cardiac dysfunction is closely linked to multiorgan involvement, including the gastrointestinal tract. Increasing evidence highlights the relevance of the gut–heart axis in HF pathophysiology, whereby intestinal hypoperfusion, congestion, and barrier dysfunction promote gut microbiota dysbiosis, systemic inflammation, and adverse cardiovascular outcomes. In parallel, the advent of novel HF therapies, particularly sodium–glucose cotransporter 2 inhibitors (SGLT2i) and the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan, has markedly improved clinical outcomes across HF phenotypes. Beyond their established cardiovascular benefits, these therapies may exert pleiotropic effects that extend to the intestinal environment and the gut microbiota. Through integrated actions on hemodynamics, neurohormonal activation, metabolic pathways, and inflammatory processes, recent data suggest that novel HF drugs may indirectly influence the gut-microbial composition and function. Conversely, the gut microbiota may modulate drug efficacy and result in interindividual variability in therapeutic responses, suggesting a bidirectional interaction between pharmacological treatment and the gut ecosystem. This narrative review summarizes current evidence of gut microbiota alterations in HF and critically examines emerging data on interactions between the gut microbiota and novel HF therapies, focusing on SGLT2 inhibitors and sacubitril/valsartan. Understanding this crosstalk may support the development of microbiota-informed, personalized therapeutic strategies in heart failure. Full article

Epilepsy is a progressive network disorder in which recurrent seizures drive maladaptive neurodevelopmental remodeling, cognitive decline, and pharmacoresistance, particularly in developmental epileptic encephalopathies. Cannabidiol (CBD) has emerged as an evidence-based adjunctive therapy for selected childhood-onset epilepsies; however, its broader clinical utility remains limited by heterogeneous responsiveness, restricted indications, and an incomplete understanding of developmental stage–specific efficacy and safety. Here, we synthesize molecular, preclinical and clinical evidence supporting the pleiotropic antiseizure and neuroprotective actions of CBD, including modulation of endocannabinoid-related G protein–coupled receptors, adenosine signaling, transient receptor potential channels, GABAergic maturation, and neuroinflammatory cascades. We highlight critical neurodevelopmental windows during which timely CBD intervention may exert disease-modifying effects by preventing pathological consolidation of hyperexcitable networks. Furthermore, we position human brain organoids as transformative translational platforms that recapitulate early human cortical development and epileptic network dynamics, enabling functional stratification of CBD-responsive phenotypes, developmental safety profiling, and precision therapeutic discovery within human-relevant neural circuits. Collectively, organoid-guided frameworks provide a mechanistic foundation for personalized, developmentally informed CBD therapy and advance precision medicine strategies aimed at modifying epileptogenic trajectories rather than solely suppressing seizures. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and depression frequently occur together. Identifying the genes that influence both MASLD and depression may facilitate the discovery of biological pathways associated with disease risk. Methods: We recruited 525 participants from Mexican American families living in the Rio Grande Valley of south Texas. We collected clinical data, biometric measurements, hepatic health assessments using Vibration-Controlled Transient Elastography (VCTE), and depression evaluations determined with the Beck Depression Inventory-II. We estimated the heritability (h²) of MASLD-related measures, depression status, aspartate aminotransferase (AST), alanine aminotransferase (ALT), the AST/ALT ratio, and Vibration-Controlled Transient Elastography measurements. For each gene, we derived a genetic endophenotype representing its expression level. We then performed functional network and gene ontology enrichment analyses to characterize the underlying protein pathways. Results: We observed significant associations between the expression of two genes, Thyroid Hormone Receptor-Associated Protein 3 (THRAP3) (h² = 0.56 [0.45, 0.67]) and ADAM Metallopeptidase with Thrombospondin Type 1 Motif 7 (ADAMTS7) (h² = 0.66 [0.55, 0.77]), with depression and multiple MASLD-related phenotypes. We identified 351 genes with expression levels significantly correlated with one or more MASLD phenotypes and depression. Among these, five genes—ADAMTS7, THRAP3, CHPM4A, RAB9A, and PDIA3—were jointly associated with three phenotypes: AST/ALT, ALT, and Controlled Attenuation Parameter (CAP kPa). Based on the Fisher Combined Test, only THRAP3 (p = 3.0 × 10⁻²) and ADAMTS7 (p = 2 × 10⁻²) were jointly significant for depression (BDI-II) and AST, ALT, AST/ALT ratio, FAST, and CAP (kPa). We present a protein–protein interaction network comprising nodes (proteins) and edges (interactions), and a gene ontology enrichment analysis of cellular components. Discussion: Our findings highlight pleiotropic genes underlying MASLD and depression. Two genes, ADAMTS7 and THRAP3, warrant further investigation as potential targets for therapeutic interventions to manage MASLD and depression among Mexican Americans. These results may improve our understanding of the pathways involved in these two diseases, advance current research, and contribute to improvements in personalized medicine. Conclusion: We identified possible shared gene expression phenotypes linking MASLD and depression, which may provide insight into a common molecular underpinning. Pathway enrichment and gene analysis were used to help refine networks and enhance our understanding of complex gene-environmental interactions and their implications for precision medicine. Full article