Radiotherapy is becoming one major therapeutics for non-small cell lung cancer (NSCLC). Identifying novel radiosensitizers will greatly increase the efficacy of radiotherapy and benefit more patients. OTU deubiquitinase 4 (OTUD4) has been reported involved in DNA damage repair pathways and could be a potential target for chemotherapy therapy. This study aimed to investigate the roles of OTUD4 in regulation of radiosensitivity of NSCLC via modulating DNA repair. The expression of OTUD4, γ-H2Ax and ATM/CHK2/p53 pathway-related signaling molecules were detected by Western blotting and QRT-PCR. The methylation of OTUD4 promoter was investigated by 5-aza-deoxycytidine treatment, methylation-specific PCR and bisulfite genomic sequencing assays. Radiosensitivity was assessed by the clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage and repair were determined by comet assay, γ-H2Ax foci staining and flow cytometry. OTUD4 is dramatically downregulated in NSCLC and its downregulation significantly correlates with poor prognosis of NSCLC patients. Promoter hypermethylation is responsible for the loss of OTUD4 expression in NSCLC cells. Overexpression of OTUD4 increases radiosensitivity of NSCLC cells exhibiting as impaired clonogenic formation ability, enhanced cell cycle arrest and increased cell apoptosis. Moreover, molecular mechanism study reveals that OTUD4 radiosensitizs NSCLC cells via ATM/CHK2/P53 signaling and inhibiting homology-directed repair of DNA double strand breaks induced by ionizing radiation. This study uncovers a tumor-suppressing role of OTUD4 and that OTUD4 is a potential radiosensitizer for NSCLC.

Pancreatic cancer is a malignant tumor of the digestive tract with a high mortality rate. Erianin has antitumor activity, but the regulatory targets and mechanism of action in pancreatic cancer are unclear. The objective of this study was to evaluate the anti-pancreatic cancer activity of Erianin and explore its underlying mechanisms. A network pharmacology approach was used to investigate the mechanism of action of Erianin in pancreatic cancer cells. Cell proliferation was analyzed using CCK8, colony-formation, and EdU proliferation assays. Cell migration was evaluated through wound healing and transwell assays, as well as determination of the protein expression levels of EMT markers and β-catenin. Apoptosis and the cell cycle were measured using flow cytometry and JC-1 staining, respectively. The protein expression levels of p-Rb, CyclinB1, P21, Cleaved-PARP, and Cleaved-Caspase3 were assessed using western blotting. RNA sequencing (RNA-seq) and bioinformatics analyses were performed to elucidate the mechanism underlying the action of Erianin in pancreatic cancer. Western blotting was used to examine the expression levels of key proteins in the AKT, JNK, and p38 MAPK signaling pathways. Molecular docking and CETSA were used to test hypotheses. The tumor-suppressive ability of Erianin in vivo was assessed using a tumor-bearing assay in nude mice. Network pharmacology revealed that Erianin inhibited pancreatic cancer through multiple pathways. Erianin significantly inhibited pancreatic cancer cell proliferation and migration while promoting intracellular ROS and inducing apoptosis. Mechanistically, Erianin inhibited pancreatic cancer cell proliferation by regulating the AKT/FOXO1 and ASK1/JNK/p38 MAPK signaling pathways. In vivo experiments showed that Erianin inhibited subcutaneous tumor growth and promoted tumor tissue apoptosis in nude mice. The component-target-pathway network revealed that Erianin exerted anti-cancer effects through multiple components, targets, and pathways. Erianin inhibited the proliferation and migration of pancreatic cancer cells and induced apoptosis through the AKT/FOXO1 and ASK1/JNK/p38 MAPK signaling pathways. These results indicate that Erianin is a promising agent for pancreatic cancer treatment.

Introduction: Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid malignancy characterized by rapid progression, resistance to conventional therapies, and poor patient prognosis. There is an urgent need for innovative therapeutic strategies. Erianin, a natural compound derived from Dendrobium, has demonstrated significant anti-tumor effects in various cancers, yet its role in ATC remains unexplored.Methods: The anti-tumor effects of erianin were assessed in vitro through assays including CCK-8, colony formation, flow cytometry, LDH release, and Western blot. RNA sequencing was conducted for gene expression analysis. Immunofluorescence and transmission electron microscopy evaluated pyroptosis markers. In vivo efficacy was validated in CAL62 xenograft mouse models using tumor growth measurement, TUNEL staining, and immunohistochemistry.Results: Erianin significantly inhibited proliferation and colony formation, induced G2/M cell cycle arrest, apoptosis, and GSDME-dependent pyroptosis in ATC cells. Mechanistically, erianin suppressed activation of the MAPK/ERK and PI3K/AKT signaling pathways. Importantly, erianin synergistically enhanced the anti-tumor efficacy of anlotinib in ATC cells. In vivo, combination therapy with erianin and anlotinib resulted in marked tumor growth suppression and increased apoptosis compared to monotherapies.Conclusion: Collectively, our study demonstrates that erianin exerts potent anti-tumor activity in ATC by simultaneously inhibiting the MAPK/ERK and PI3K/Akt signaling pathways, thereby inducing apoptosis and GSDME-dependent pyroptosis. Furthermore, the synergistic interaction between erianin and anlotinib significantly enhances therapeutic efficacy. These findings position erianin as a promising candidate for the treatment of ATC, offering novel therapeutic insights and supporting further clinical investigations.

Telomere length (TL) has been implicated in the risk assessment of numerous cancers in observational studies. Nevertheless, the relationship between TL and malignant lymphoma remains unclear, displaying inconsistent patterns across different studies. A summary dataset for genome-wide association study of TL and malignant lymphoma was acquired from the OpenGWAS website. An extensive 2-sample Mendelian randomization (MR) analysis was performed, encompassing various methodologies such as MR-Egger, weighted median, weighted mode, simple mode, and the primary method of inverse-variance weighting (IVW). Sensitivity evaluations were performed using the Cochran Q test, MR-Egger regression, and leave-one-out analysis. The main method IVW revealed that TL substantially increased the risk of Hodgkin lymphoma (HL; odds ratio [OR] = 2.135; 95% confidence interval [CI] = 1.181–3.859; P = .012). Both the IVW and weighted median methods indicated statistical associations between genetically predicted TL and other types of non-HL (OR = 1.671, 95% CI = 1.009–2.768, P = .045; OR = 2.310, 95% CI = 1.033–5.169, P = .042). However, there was no association between TL and diffuse large B-cell lymphoma, follicular lymphoma, or mature T/natural Killer-cell lymphoma, and sensitivity analysis revealed no heterogeneity or horizontal pleiotropy, indicating that the causal effect was robust. Our study shows that TL plays different roles in different types of lymphomas. A longer TL significantly increases the risk of HL and other types of non-HL.

The factors associated with early death in primary hepatopancreatobiliary non-Hodgkin’s lymphoma (PHPB-NHL) patients have not been previously investigated. This study aimed to develop and validate a population-based nomogram for early death prediction in PHPB-NHL patients. Data on PHPB-NHL patients diagnosed from 2000 to 2021 were collected from the Surveillance, Epidemiology and End Results database. Patients diagnosed between 2000 and 2015 formed the training cohort, while those from 2016 to 2021 represented the validation cohort. Univariate and multivariate logistic regression analyses identified factors affecting early death, which were used to create a nomogram. The discriminatory ability, calibration, and clinical utility of the nomogram were evaluated using the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis, respectively. The Surveillance, Epidemiology and End Results database identified 2802 PHPB-NHL patients from 2000 to 2021, with eligible patients divided into a training cohort (1240) and a validation cohort (509). In the training cohort, 29.4% (365/1240) experienced early death. Factors for early death included age, race, primary site, histological type, surgery, radiotherapy, chemotherapy, median household income, and time from diagnosis to treatment. A nomogram based on these factors showed good discrimination (AUC 0.815, 95% CI: 0.789–0.842) and was validated internally (optimism-corrected AUC 0.805, 95% CI: 0.780–0.831). Calibration curves showed strong agreement between predictions and actual outcomes. The validation cohort also showed good discrimination (AUC 0.827, 95% CI: 0.787–0.867) and calibration. Decision curve analysis indicated a positive net benefit. We developed and validated a nomogram to predict early death in PHPB-NHL patients, demonstrating strong predictive accuracy and clinical utility.