Bioinformatic Identification and Preliminary Validation of TP53, TGFB1, and NFE2L2 as Potential Ferroptosis-Related Regulators in Pancreatic Adenocarcinoma.
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引用次数: 0
Abstract
Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor with very poor prognosis for patients. Ferroptosis, as a novel cell death mechanism, brings a new direction for PAAD therapeutic research.
Methods: Ferroptosis-related differentially expressed genes were identified by bioinformatic analysis of the FerrDb, TCGA, and GTEx databases. A series of analyses, including functional enrichment, protein-protein interaction (PPI) networking, survival analysis, and immune infiltration profiling, were performed to screen for and characterize hub genes. Subsequently, the expression of key hubs-NFE2L2 (NRF2), TGFB1, and TP53-was validated in PDAC patient tissues and cell lines using qRT-PCR and Western blot. Their biological functions were investigated via shRNA-mediated knockdown in BxPC-3 cells, followed by assays for cell migration (wound healing, transwell) and ferroptosis (ROS, MDA, GSH/GSSG).
Results: Bioinformatic analysis identified 221 ferroptosis-related DEGs. NFE2L2, TGFB1, and TP53 emerged as core hub genes whose high expression correlated with poor patient survival and specific immune infiltration patterns. Experimental validation confirmed that NRF2, TGFβ1, and TP53 proteins were significantly upregulated in PDAC tissues compared to adjacent normal tissues. Functionally, knockdown of NFE2L2 and TGFB1 suppressed PDAC cell migration, whereas TP53 knockdown enhanced it. Inversely, NFE2L2 knockdown promoted ferroptosis (increased ROS and MDA, decreased GSH), while knockdown of both TGFB1 and TP53 inhibited ferroptosis.
Conclusion: TP53, TGFB1, and NRF2 are key ferroptosis-related regulators in PAAD, influencing tumor progression, ferroptosis sensitivity, and immune contexture. These findings provide new insights and potential targets for ferroptosis-based therapies in PAAD.
期刊介绍：
Pharmacogenomics and Personalized Medicine is an international, peer-reviewed, open-access journal characterizing the influence of genotype on pharmacology leading to the development of personalized treatment programs and individualized drug selection for improved safety, efficacy and sustainability.
In particular, emphasis will be given to:
Genomic and proteomic profiling
Genetics and drug metabolism
Targeted drug identification and discovery
Optimizing drug selection & dosage based on patient''s genetic profile
Drug related morbidity & mortality intervention
Advanced disease screening and targeted therapeutic intervention
Genetic based vaccine development
Patient satisfaction and preference
Health economic evaluations
Practical and organizational issues in the development and implementation of personalized medicine programs.
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