Radiation‐induced intestinal injury is a common and critical complication of radiotherapy for pelvic or abdominal tumors, with limited therapeutic strategies and effectiveness. Sitagliptin, a dipeptidyl peptidase IV (DPP4) inhibitor, has previously been reported to alleviate total body irradiation‐ (TBI‐) induced damage of hematopoietic system in mice, but its effect on radiation‐induced intestinal injury remains unclear. In this study, we confirmed that Sitagliptin could not only protect mice from death and weight loss caused by whole abdominal irradiation (WAI) but also improve the morphological structure of intestine and the regeneration ability of enterocytes. In addition, Sitagliptin significantly inhibited the production of radiation‐induced proinflammatory cytokines and reduced the number of apoptotic intestinal epithelial cells and γ‐H2AX expression. In vitro, we demonstrated that Sitagliptin protected HIEC‐6 cells from ionizing radiation, resulting in increased cell viability and reduced DNA damage. Mechanistically, the radiation protection of Sitagliptin might be related to the upregulation of NRF2 level and the decrease of NLRP3 inflammasome activity. Importantly, Sitagliptin significantly restored radiation‐induced changes in bacterial composition. In conclusion, our results suggested that Sitagliptin could reduce WAI‐induced intestinal injury in mice, which may provide novel therapeutic strategy for radiation‐induced intestinal injury.

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies (GWAS) have been linked to expression quantitative trait loci (eQTL) in previous studies, further work is needed to better elucidate the relationship to other genetic regulatory mechanisms, such as splicing QTLs (sQTL). Here, we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 non–small cell lung cancer (NSCLC) samples from The Cancer Genome Atlas. The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions, genetic regulatory elements, RNA-binding protein (RBP) binding sites, and known NSCLC risk loci. In addition, target genes affected by sQTLs (sGenes) were involved in multiple processes in cancer, including cell growth, apoptosis, metabolism, immune infiltration, and drug responses, and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform (GSTO2-V1) and lower expression of the truncated GSTO2 isoform (GSTO2-V2), which was induced by RBP quaking (QKI). Mechanistically, compared with GSTO2-V1, GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall, this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential. Significance: Analysis of sQTL reveals the role of genetically driven mRNA splicing alterations in NSCLC risk and elucidates that rs156697 variant impacts risk by altering GSTO2 splicing.

Background: Copine1 (CPNE1), the first discovered CPNE1 family member, participates in the process of carcinogenesis and development of diverse tumors. Our study aimed to investigate the expression and prognostic value of CPNE1 gene in hepatocellular carcinoma (HCC), to explore its functional network in HCC and its effects on biological behaviors. Methods: HCCDB, CCLE, HPA and LinkedOmics online databases were used to explore the expression of CPNE1 gene and analyze the co-expression network of CPNE1 in hepatocellular carcinoma. Gene set enrichment analysis (GSEA) was used for GO functional annotation, KEGG pathway enrichment analysis and regulators of CPNE1 networks in LIHC. HepG2 and MHCC-97H cells were selected to construct CPNE1 knockdown cell lines by transfection with siRNA, and Hep3B cell was selected to construct CPNE1 overexpression cell line by transfection with plasmid. The effect of CPNE1 on the proliferation of hepatocellular carcinoma cells was examined by CCK8 assay and clone formation assay; the effect of CPNE1 on the migration ability of hepatocellular carcinoma cells was assessed by cell scratch assay and Transwell cell migration assay; finally, the expression of related signaling pathway proteins was examined by Western Blot. The correlation of CPNE1 expression with immune infiltration and immune checkpoint molecules in HCC tissues was analyzed using TIMER online database and GSEA. Results: CPNE1 was highly expressed in HCC tissues and significantly correlated with sex, age, cancer stage and tumor grade. Overall survival (OS) was significantly lower in patients with high CPNE1 expression than in patients with low CPNE1 expression, and CPNE1 could be used as an independent prognostic indicator for HCC. Knockdown of CPNE1 gene inhibited the AKT/P53 pathway, resulting in decreased proliferation, migration and invasion of HCC cells. Overexpression of CPNE1 gene showed the opposite results. The level of CPNE1 expression in HCC was significantly and positively correlated with the level of infiltration of B cells, CD8⁺ T cells, CD4⁺ T cells, macrophages, neutrophils, and dendritic cells (P < 0.001). GSEA results also showed that CPNE1 of LIHC was involved in some immune response regulating signaling pathways. Conclusions: Our study firstly found the expression of CPNE1 was significantly higher in LIHC tissues than in normal liver tissues, and high CPNE1 expression was associated with poor prognosis. In addition, we identified the possible mechanism by which CPNE1 functioned in LIHC. CPNE1 influenced AKT/P53 pathway activation and LIHC cell proliferation and migration. There was a significant correlation between CPNE1 expression and tumor immune infiltration in LIHC.

Pulmonary fibrosis (PF) is a group of chronic progressive lung diseases characterized by irreversible remodeling of lung tissue structure, abnormal proliferation of fibroblasts, and excessive deposition of extracellular matrix (ECM), among which idiopathic pulmonary fibrosis (IPF) is the most typical subtype. Currently, the only two clinically approved therapeutic drugs (nintedanib and pirfenidone) can only partially slow disease progression without reversing fibrotic lesions, and are associated with varying degrees of adverse effects. Oxidative stress, defined as a pathological imbalance between systemic oxidant and antioxidant systems, has been substantiated by extensive research as a pivotal mechanism driving the pathogenesis and progression of pulmonary fibrosis. This review summarizes the regulatory mechanisms of oxidative stress in pulmonary fibrosis, with a focus on its critical role in inducing and promoting fibrosis through relevant target cells and signaling pathways. We also specifically highlight the latest progress and challenges in therapeutic strategies targeting oxidative stress, and discuss next-generation therapies, including the modulation of endogenous antioxidant pathways, supplementation of exogenous antioxidants, as well as nanomaterials, exosomes, and combination therapies. We hope this review will deepen the understanding of oxidative stress and pulmonary fibrosis, and provide new directions for improving the clinical efficacy of oxidative stress-targeted therapies.

Background: Hepatocellular carcinoma (HCC) is an extremely malignant cancer with poor survival. H2AFY gene encodes for a variant of H2A histone, and it has been found to be dysregulated in various tumors. However, the clinical value, biological functions and correlations with immune infiltration of H2AFY in HCC remain unclear.Methods: We analyzed the expression and clinical significance of H2AFY in HCC using multiple databases, including Oncomine, HCCDB, TCGA, ICGC, and so on. The genetic alterations of H2AFY were analyzed by cBioPortal and COSMIC databases. Co-expression networks of H2AFY and its regulators were investigated by LinkedOmics. The correlations between H2AFY and tumor immune infiltration were explored using TIMER, TISIDB databases, and CIBERSORT method. Finally, H2AFY was knocked down with shRNA lentiviruses in HCC cell lines for functional assays in vitro.Results: H2AFY expression was upregulated in the HCC tissues and cells. Kaplan–Meier and Cox regression analyses revealed that high H2AFY expression was an independent prognostic factor for poor survival in HCC patients. Functional network analysis indicated that H2AFY and its co-expressed genes regulates cell cycle, mitosis, spliceosome and chromatin assembly through pathways involving many cancer-related kinases and E2F family. Furthermore, we observed significant correlations between H2AFY expression and immune infiltration in HCC. H2AFY knockdown suppressed the cell proliferation and migration, promoted cycle arrest, and apoptosis of HCC cells in vitro.Conclusion: Our study revealed that H2AFY is a potential biomarker for unfavorable prognosis and correlates with immune infiltration in HCC.

Background. Lung adenocarcinoma (LUAD) represents the most common histological subtype of lung cancer. Redox plays a significant role in oncogenesis and antitumor immunity. In this study, we aimed to investigate the prognostic redox-associated genes and construct a redox-based prognostic signature for LUAD. Materials and Methods. A discovery cohort containing 479 LUAD samples from The Cancer Genome Atlas (TCGA) was analyzed. We identified prognostic redox-associated genes by weighted correlation network analysis (WGCNA) and univariate Cox regression analysis to construct a prognostic model via least absolute shrinkage and selection operator (LASSO)-multivariate Cox regression analyses. The performance of the redox-based model was validated in the TCGA cohort and an independent cohort of 456 samples by Cox regression analyses, log-rank test, and receiver operating characteristic (ROC) curves. Correlations of the model with clinicopathological variables and lymphocyte infiltration were assessed. Gene set enrichment analysis (GSEA) was used to clarify the underlying mechanism of the prognostic model. We constructed a nomogram based on the model and created calibration curves to show the accordance between actual survival and predicted survival of the nomogram. Results. Stepwise analyses identified 6 prognostic redox-associated genes of LUAD and constructed a prognostic model that performed well in both the discovery and validation cohorts. The model was found to be associated with tumor stage, mutation of TP53 and EGFR, and lymphocyte infiltration. The model was mainly involved in the regulation of the cell cycle, DNA replication and repair, NADH metabolism, and the p53 signaling pathway. Calibration curves showed the high predictive accuracy of the nomogram. Conclusions. This study explored the role of redox-associated genes in LUAD and constructed a prognostic model of LUAD. The signature was also associated with tumor progression and therapeutic response to immunotherapy. These findings contributed to uncovering the underlying mechanism and discovering novel prognostic predictor of LUAD.