Cancer Cell, Год журнала: 2024, Номер unknown
Опубликована: Ноя. 1, 2024
Язык: Английский
Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)
Опубликована: Май 2, 2025
Abstract Background Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctanoic acid (PFOA) perfluorooctane sulfonate (PFOS), are synthetic chemicals known for their widespread use environmental persistence. These compounds have been increasingly linked to hepatotoxicity the development of hepatocellular carcinoma (HCC). However, molecular mechanisms by which PFAS contribute HCC remain underexplored. Methods This study employs a multi-omics approach that combines network toxicology, integrated machine learning, single-cell RNA sequencing, spatial transcriptomics, experimental validation, docking simulations uncover through exposure drives HCC. We analyzed publicly available transcriptomic data from several cohorts used differential gene expression analysis identify targets associated with both constructed protein–protein interaction (PPI) survival risk model, PFAS-related signature (PFASRHSig), based on learning prognostic biomarkers, goal identifying core in progression prognosis. RT-qPCR immunohistochemical (IHC) staining were validate levels tumor normal tissues. Molecular conducted assess binding affinities between selected target proteins. Results Functional enrichment studies revealed metabolic signaling pathways, actively involved lipid, glucose, drug metabolism, etc. Through PPI analysis, we identified six genes, APOA1, ESR1, IGF1, PPARGC1A, SERPINE1, PON1, serve as further validated via bulk RNA-seq, patterns across various cell types microenvironment. The results IHC consistent silico findings. strong these targets, supporting potential roles PFAS-induced hepatocarcinogenesis. Conclusions Our highlights key pathways liver carcinogenesis proposes robust model (PFASRHSig) findings provide new insights into toxicity offer therapeutic mitigating health risks exposure. Collectively, our help advancing clinical applications providing disease interventions.
Язык: Английский
Процитировано
0
Cancer Immunology Immunotherapy, Год журнала: 2025, Номер 74(7)
Опубликована: Май 27, 2025
Язык: Английский
Процитировано
0
Frontiers in Immunology, Год журнала: 2025, Номер 16
Опубликована: Май 27, 2025
Background Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Despite therapeutic advances, there is critical need to identify novel, effective, and safe drug targets improve precision treatment strategies. Methods We developed multi-layered framework integrating Mendelian randomization (MR), colocalization analysis, genome-wide association study (GWAS) data, expression quantitative trait loci (eQTLs) prioritize causal druggable genes in CRC. Single-cell bulk RNA sequencing were used characterize gene within the tumor microenvironment. Phenome-wide studies (PheWAS) assessed off-target effects, repurposing potential was evaluated using OpenTargets, DrugBank, DGIdb. Validation key performed through RT-qPCR immunohistochemistry (IHC) CRC patient samples. Results Out 4,479 genes, MR analysis identified 47 candidates significantly associated with risk. Six (TFRC, TNFSF14, LAMC1, PLK1, TYMS, TSSK6) demonstrated strong signals further validated across replication datasets subtype-stratified analyses. PheWAS revealed minimal effects for these genes. Notably, several have already been targeted by existing or investigational drugs, suggesting repurposing. These exhibited distinct patterns stromal cell types differentially expressed versus normal tissues. Among them, an immune modulator, particularly involved regulating T activation Conclusion This identifies validates six promising CRC, providing foundation future preclinical studies. findings open avenues advancing oncology strategies treatment, contributing development more effective personalized approaches.
Язык: Английский
Процитировано
0
Drug Resistance Updates, Год журнала: 2025, Номер 82, С. 101261 - 101261
Опубликована: Май 29, 2025
Язык: Английский
Процитировано
0
Cancer Communications, Год журнала: 2025, Номер unknown
Опубликована: Май 29, 2025
Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a challenging cancer with an increasing incidence. The Phase III TOPAZ‐1/KEYNOTE‐966 study demonstrated chemo‐immunotherapy (CIT) as significant advancement, potentially replacing traditional chemotherapy for advanced biliary tract cancer. Ferroptosis crucial process that affects cell survival and therapy resistance. Although AKT hyperactivation prevalent in numerous cancers, including ICC, its role ferroptosis resistance remains unclear. This explored whether targeting can enhance CIT response rates, specifically ICC patients hyperactivation. Methods In vivo metabolic CRISPR screening Kras G12D /Tp53 −/− mouse model was used to identify primary regulators of during (gemcitabine, cisplatin, anti‐mouse programmed death 1 ligand 1). Phosphoenolpyruvate carboxykinase (PCK1) assessed treatment preclinical models under activation levels. Molecular biochemical techniques were explore PCK1‐related mechanisms AKT‐hyperactivated ICC. Results Under condition, phosphorylated PCK1 (pPCK1) promoted reprogramming, enhancing ubiquinol menaquinone‐4 synthesis through the mevalonate (MVA) pathway. cascade mediated by pPCK1‐pLDHA‐SPRINGlac axis. Inhibiting phosphorylation or using simvastatin significantly augmented efficacy models. Clinical data further indicated (pAKT)‐pPCK1 levels might serve biomarker predict Conclusion identified pAKT‐pPCK1‐pLDHA‐SPRINGlac axis novel mechanism driving associating glycolytic MVA flux reprogramming. Targeting this axis, statin‐based therapies, may offer strategy sensitize cells improve outcomes.
Язык: Английский
Процитировано
0
Trends in Immunology, Год журнала: 2024, Номер unknown
Опубликована: Дек. 1, 2024
Язык: Английский
Процитировано
1
Cancer Cell, Год журнала: 2024, Номер unknown
Опубликована: Ноя. 1, 2024
Язык: Английский
Процитировано
0