Yanggang Hong

Cryptorchidism is the most common congenital anomaly requiring pediatric surgical correction. Although surgical repositioning of the undescended testis (orchidopexy) is effective anatomically, the molecular and cellular mechanisms underlying ongoing testicular damage after surgery remain poorly understood. We established a surgically induced unilateral cryptorchidism model in adult mice, collected testicular tissues at day 0, 3, 7, 10, and 14 after induction, and performed bulk RNA sequencing on samples collected at day 0, 3, and 7. Differentially expressed genes (DEGs) were analyzed for pathway enrichment and protein-protein interactions. Cell-type-specific gene expression patterns were evaluated using publicly available single-cell RNA-seq data. Histological evaluation was performed to validate tissue-level changes. Transcriptomic profiling revealed rapid upregulation of extracellular matrix remodeling and inflammatory signaling by day 3, primarily in somatic cells such as Sertoli and peritubular myoid cells. By day 7, we observed activation of pro-apoptotic and TGF-β signaling pathways. Key genes including Ddr1, Ltbp1, and Spp1 were enriched in somatic compartments. Histology confirmed progressive seminiferous tubule disorganization and germ cell depletion, consistent with somatic cell-driven structural deterioration. This study provides hypothesis-generating evidence that somatic cell dysfunction may be an early feature of cryptorchidism-associated testicular injury in this adult mouse model. These findings identify candidate genes and pathways for further investigation. Validation in developmental cryptorchidism models and human tissue will be required to establish clinical relevance.

Chronic obstructive pulmonary disease (COPD) is a complex disorder driven by both genetic susceptibility and environmental exposures. Endocrine-disrupting

Background: Multidimensional sleep health, encompassing duration, snoring, chronotype, insomnia symptoms, and daytime sleepiness, is associated with various chronic diseases. However, its relationship with depression risk, especially the underlying molecular mechanisms across different levels of genetic susceptibility, remains unclear. Methods: In this prospective cohort study, we analyzed data from 36,852 UK Biobank participants, integrating multidimensional sleep scores, plasma proteomic data covering 2,911 proteins, and polygenic risk scores (PRS) for depression. Sleep‐related proteins were identified via elastic net regression, and their associations with incident depression were assessed using Cox proportional hazards models. Mediation and interaction analyses were conducted to explore the role of proteomic features and their effect modification by genetic risk. Results: Seventy‐three plasma proteins were selected by elastic net as sleep‐related proteomic features, mainly involving immune regulation, neural signaling, metabolic homeostasis, and extracellular matrix remodeling. The proteomic score derived from these features was positively correlated with sleep health ( r = 0.234, p < 1 × 10 ⁻¹⁰⁰ ). Healthy sleepers had a lower risk of depression (HR = 0.553, 95% CI: 0.454–0.674, p < 0.001), as did those with higher proteomic scores (HR = 0.660, 95% CI: 0.566–0.770, p < 0.001). Mediation analysis suggested that the proteomic signature statistically accounted for a modest proportion of the observed association between sleep health and incident depression. A significant additive interaction was observed between unhealthy sleep and high genetic risk (RERI = 0.280, 95% CI: 0.022–0.538). Conclusion: This study characterizes the plasma proteomic profile of multidimensional sleep health and identifies sleep‐associated proteomic signatures related to incident depression across levels of genetic susceptibility. These findings highlight potential biological pathways for further investigation and require independent replication and causal validation before clinical interpretation.

Epigenetic age acceleration (EAA) reflects biological aging processes beyond chronological age and is associated with morbidity and mortality. However, the causal gene regulatory mechanisms underlying epigenetic age remain unclear. Here, we integrated single‐cell expression quantitative trait loci (sc‐eQTL) data across 14 immune cell types with Mendelian randomization (MR) and Bayesian colocalization to identify eGenes whose cell‐type‐specific expression causally influences four major epigenetic clocks: IEAA, HannumAge, GrimAge, and PhenoAge. We identified 58 unique eGenes with strong evidence of causality, including ATM , ENO1 , DDX5 , and PSMB9 , with effects often confined to specific immune lineages such as CD8 T and NK cells. Functional enrichment analysis revealed that these eGenes are involved in immune regulation, NF‐κB signaling, and mitochondrial metabolism. Phenome‐wide association studies (PheWAS) further linked top eGenes, particularly ATM and DDX5 , to a spectrum of aging‐related traits, including metabolic and immune disorders. Our findings highlight the importance of immune‐cell‐specific gene regulation in shaping biological aging and provide candidate targets for future aging interventions.

Parkinson’s disease (PD) is a complex neurodegenerative disorder with growing evidence suggests peripheral immunity plays a role in its pathogenesis. However, the specific peripheral immune cell types and gene expression profiles associated with PD remain unclear. In this study, we integrated single-cell expression quantitative trait loci (sc-eQTL) data from 14 immune cell types in the OneK1K cohort with large-scale genome-wide association study (GWAS) data for PD. Using Mendelian randomization (MR) and Bayesian colocalization analyses, we identified 28 immune-cell-specific eGenes with significant associations to PD risk, among which 24 showed strong or moderate evidence of shared genetic signals. Notable candidates included FDFT1, ARSA, CTSB, and HLA-DQA1, each displaying cell-type-specific associations in CD4⁺ T cells, CD8⁺ T cells, B cells, and monocytes. Replication using an independent sc-eQTL dataset from the DICE project confirmed consistent findings for several eGenes. Additional validation through peripheral blood single-cell RNA sequencing (scRNA-seq) revealed distinct expression patterns and significant changes in PD patients. Phenome-wide association studies (PheWAS) showed multiple associations with immune-related traits and minimal associations with unrelated traits, indicating a favorable safety profile for therapeutic targeting. Drug repurposing analysis identified several candidate compounds, including felodipine, amodiaquine, alprazolam, and tetrandrine, some of which are predicted to cross the blood-brain barrier. Molecular docking simulations further supported strong binding interactions between these compounds and PD-associated targets such as CTSB and ARSA. This integrative approach highlights key immune-cell-specific genes involved in PD and proposes several repurposable drugs with central nervous system potential, paving the way for more targeted therapeutic strategies.

Migraine is a highly prevalent neurological disorder with complex pathophysiology and limited treatment efficacy. Emerging evidence suggests immune cell involvement in migraine, but the specific regulatory mechanisms remain unclear. This study aimed to identify immune cell-type-specific genetic drivers of migraine and prioritize potential therapeutic targets. We conducted a Mendelian randomization (MR) analysis integrating single-cell expression quantitative trait loci (sc-eQTL) data from 14 immune cell types with large-scale genome-wide association studies (GWAS) of migraine. Colocalization analysis, protein-protein interaction (PPI) networks, linkage disequilibrium score regression (LDSC), phenome-wide association studies (PheWAS), and drug repurposing databases were utilized to validate findings and assess therapeutic potential and safety. We identified 25 immune cell-specific eGenes causally associated with migraine, including CDC42, NELFCD, HOXB3, HAX1, and FHL3. Several genes, such as CDC42 and HAX1, were implicated across multiple immune cell types. Subtype-specific analyses revealed differential gene effects in migraine with aura (MA) and without aura (MO). Genetic correlation and pleiotropy analyses linked eGenes to comorbid traits such as depression, gastrointestinal disorders, and blood pressure. PheWAS suggested minimal adverse associations for prioritized genes like GINM1 and TMA7. Drug repurposing identified FDA-approved agents, including hydroxychloroquine sulfate (NELFCD) and bazedoxifene (CDC42), as potential migraine therapies. This study reveals immune cell-specific genetic contributors to migraine and highlights druggable targets for therapeutic development. Integrating sc-eQTL with multi-omics and pharmacological data provides a novel framework for precision medicine in migraine.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by poor prognosis, strong resistance to therapy, and a dense immunosuppressive tumor microenvironment (TME). A small subset of cells known as cancer stem cells (CSCs), or tumor-initiating cells (TICs), are increasingly recognized as key contributors to tumor initiation, metastasis, immune evasion, and treatment failure. These cells are defined by their self-renewal capacity, plasticity, and resistance to chemotherapeutic and targeted therapies. Pancreatic cancer stem cells (PaCSCs) are maintained by specific surface markers (CD44, CD133, EpCAM, ALDH1A1) and regulated by stemness-associated signaling pathways such as Wnt/β-catenin, Notch, Hedgehog, and TGF-β. Their survival is further enhanced by metabolic reprogramming, including shifts between glycolysis and oxidative phosphorylation and the activation of ROS-detoxifying enzymes. Importantly, PaCSCs reside in specialized niches formed by hypoxia, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and extracellular matrix (ECM) components that together shield them from immune clearance and promote therapeutic resistance. This review outlines the molecular features and functional roles of PaCSCs, their interaction with the TME, and recent advances in targeting this CSC-stroma network. Promising therapeutic strategies, such as CAR-T/NK cell therapies, epigenetic inhibitors, and combination regimens with checkpoint blockade or stromal modulators, are discussed in the context of ongoing clinical trials. Targeting both CSCs and their supportive microenvironment is emerging as a necessary strategy to overcome resistance and improve clinical outcomes in PDAC.

Aging is a complex process influenced by genetic, environmental, and psychiatric factors. Recent evidence suggests that epigenetic age acceleration (EAA), a biomarker of biological aging, may be linked to psychiatric disorders, yet the causal direction remains unclear. This study employed a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationships between EAA (IEAA, HannumAA, GrimAA, PhenoAA) and ten psychiatric disorders. Genome-wide association study (GWAS) summary statistics from large European ancestry cohorts were used, and sensitivity analyses were conducted to ensure robustness. Forward MR analysis demonstrated that PhenoAge acceleration (PhenoAA) significantly increased the risk of attention-deficit hyperactivity disorder (ADHD) (OR = 1.043, P = 0.004), suggesting that cumulative biological aging may contribute to neurodevelopmental vulnerabilities. Conversely, Hannum age acceleration (HannumAA) was associated with a protective effect against obsessive-compulsive disorder (OCD) (OR = 0.904, P = 0.004). Reverse MR analysis revealed that autism spectrum disorder (ASD) was linked to a decrease in intrinsic epigenetic age acceleration (IEAA) (OR = 0.811, P = 0.027), while major depressive disorder (MDD) significantly increased both HannumAA (OR = 1.318, P = 0.005) and IEAA (OR = 1.226, P = 0.049). These findings suggest that psychiatric conditions may both influence and be influenced by biological aging processes. This study reveals a bidirectional link between psychiatric disorders and biological aging, showing that early-life mental health conditions may accelerate epigenetic aging and increase age-related disease risk. As psychiatric disorders are recognized as aging risk factors, these findings highlight the need for research on aging-targeted interventions in psychiatric populations.