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.

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.

Female infertility, a global health concern affecting up to 12 % of women, is influenced by genetic, hormonal, and environmental factors. Among environmental contributors, endocrine-disrupting chemicals (EDCs), which interfere with hormonal systems, have gained attention for their potential impact on reproductive health. This study used Mendelian randomization (MR) and colocalization analyses to explore the causal relationships between gene expression influenced by EDCs and female infertility. We identified 4207 EDC-related genes from The Endocrine Disruption Exchange (TEDX) database and Comparative Toxicogenomics Database (CTD), and analyzed their potential causal effects on female infertility using genome-wide association data. A total of five genes showed significant associations with infertility risk, with SULT1B1, MASTL, and TTC39C linked to increased risk, and ESR1 and AKAP13 associated with a protective effect. Colocalization analysis revealed that four of these genes (ESR1, TTC39C, AKAP13, and SULT1B1) shared causal variants with infertility, strengthening the MR findings. Additionally, interactions between these genes and key EDCs like bisphenol A (BPA), tetrachlorodibenzodioxin (TCDD), and sodium arsenite highlighted complex molecular mechanisms through which environmental exposures influence fertility. These findings provide new insights into the gene-environment interactions contributing to female infertility and offer potential targets for interventions to mitigate the harmful effects of EDCs on reproductive health.

Male infertility is a growing global health concern increasingly linked to environmental exposure to endocrine-disrupting chemicals (EDCs). However, the specific molecular mechanisms by which EDCs contribute to impaired reproductive function remain unclear. In this study, we systematically identified EDC-related genes using curated chemical-gene interaction databases and assessed their causal roles in male infertility through Mendelian randomization (MR) and colocalization analyses, utilizing large-scale cis-eQTL and GWAS datasets. A total of six genes, RHEB, PARP1, SLTM, PLIN1, PEX11A, and SDCBP, showed strong evidence of causal relationships and shared genetic variants associated with both gene expression and infertility traits. Single-cell RNA sequencing of human testicular tissue revealed that these genes are predominantly expressed in germ cells and are significantly dysregulated in non-obstructive azoospermia (NOA) samples, supporting their functional relevance. Additionally, environmental mapping indicated that several widely encountered EDCs, including bisphenol A (BPA) and its analogs, triphenyl phosphate (TPP), and sodium arsenite, interact with multiple candidate genes. These findings provide mechanistic insight into how chemical exposures can dysregulate gene expression in testicular cells and contribute to male infertility, highlighting the need for targeted environmental risk assessments and regulatory strategies.