Dysregulation of G6PD involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. The PPP plays a pivotal role in meeting the anabolic demands of cancer cells. However, the detailed underlying molecular mechanisms of targeting the G6PD‐regulated PPP in breast cancer remain unclear. In this study, we aimed to elucidate the molecular pathways mediating the effects of G6PD on cancer progression. Clinical sample analysis found that the expression of G6PD in breast cancer patients was higher than that in normal controls, and patients with higher G6PD expression had poor survival. Gene knockdown or inhibition of G6PD by 6‐AN in MCF‐7 and MDA‐MB‐231 cells significantly decreased cell viability, migration, and colony formation ability. G6PD enzyme activity was inhibited by 6‐AN treatment, which caused a transient upregulation of ROS. The elevated ROS was independent of cell apoptosis and thus associated with abnormal activated autophagy. Accumulated ROS levels induced autophagic cell death in breast cancer. Inhibition of G6PD suppresses tumour growth in preclinical models of breast cancer. Our results indicate that targeting the G6PD‐regulated PPP could restrain tumours in vitro and in vivo, inhibiting G6PD caused cell death by over‐activating autophagy, therefore leading to inhibited proliferation and tumour formation.

Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia characterized by chronic progressive fibrosis, ultimately leading to respiratory failure and early mortality. Although not fully explored, the major causative factors in IPF pathogenesis are dysregulated fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) deposited by myofibroblasts differentiated from pulmonary fibroblasts. More signalling pathways, including the PI3K-Akt-mTOR and autophagy pathways, are involved in IPF pathogenesis. Niclosamide ethanolamine salt (NEN) is a highly effective multitarget small-molecule inhibitor reported in antitumor studies. Here, we reported that in an IPF animal model treated with NEN for 14 days, attractive relief of pulmonary function and hydroxyproline content were observed. To further explore, the therapeutic effect of NEN in IPF and pathological changes in bleomycin-challenged mouse lung sections were assessed. Additionally, the effects of NEN on abnormal proliferation and ECM production in IPF cell models established with TGF-β1-stimulated A549 cells or DHLF-IPF cells were studied. In nonclinical studies, NEN ameliorated lung function and histopathological changes in bleomycin-challenged mice, and the lung hydroxyproline content was significantly diminished with NEN treatment. In vitro, NEN inhibited PI3K-mTORC1 signalling and arrested the cell cycle to prevent uncontrolled fibroblast proliferation. Additionally, NEN inhibited TGF-β1-induced epithelial–mesenchymal transition (EMT) and ECM accumulation via the mTORC1-4EBP1 axis. Furthermore, NEN-activated noncanonical autophagy resensitized fibroblasts to apoptosis. The above findings demonstrated the potential antifibrotic effect of NEN mediated via modulation of the PI3K-mTORC1 and autophagy pathways. These data provide strong evidence for a therapeutic role for NEN in IPF.

Background: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer and the major phenotype of BRCA related hereditary breast cancer. Platinum is a promising chemotherapeutic agent for TNBC. However, its efficacy for breast cancer with BRCA germline mutation remains inconclusive. Here we present a meta-analysis to evaluate the effect of platinum agents for breast cancer patients with BRCA mutation in neoadjuvant setting. Materials and Methods: Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for relevant studies on neoadjuvant platinum treatment and BRCA related breast cancer. Fixed- and random-effect models were adopted for meta-analyses. Heterogeneity investigation was conducted by sensitivity and subgroup analyses. Publication bias was evaluated by funnel plot and Begg’s test. Results: In all, five studies with 363 patients were included for meta-analysis. The pooled pathological complete response (pCR) rates were 43.4% (59/136) and 33.9% (77/227) for platinum and control groups, respectively. Adding platinum to neoadjuvant regimen did not significantly improved pCR rate (odds ratio [OR]: 1.340, 95% confidence interval [CI] = 0.677–2.653, p = 0.400). Sensitivity analyses also revealed platinum did not significantly increase pCR rate in either TNBC or HER2- patients (TNBC subgroup: OR: 1.028, 95% CI = 0.779–1.356, p = 0.846; HER2- subgroup: OR: 0.935, 95% CI = 0.716–1.221, p = 0.622). Conclusions: Our meta-analysis suggested that the addition of platinum to neoadjuvant chemotherapy did not significantly improve pCR rate for patients with BRCA mutations. Further large-scale randomized control trial with survival data may provide more robust evidence on therapeutic value of platinum for breast cancer neoadjuvant treatment.

Background: The prognostic and clinical value of tumor-associated macrophages (TAMs) in patients with breast cancer (BCa) remains unclear. We conducted the current meta-analysis to systematically evaluate the association of CD68+ and CD163+ TAM density with the prognosis and clinicopathologic features of BCa patients.Methods: Searches of Web of Science, PubMed, and EMBASE databases were performed up to January 31, 2022. The meta-analysis was conducted using hazard risks (HRs) and 95% confidence intervals (CIs) for survival data including overall survival (OS), disease-free survival (DFS), and BCa specific survival. Sensitivity and meta-regression analyses were also conducted to identify the robustness of the pooled estimates.Results: Our literature search identified relevant articles involving a total of 8,496 patients from 32 included studies. Our analysis indicates that a high CD68+ TAM density in the tumor stoma was significantly linked with poor OS (HR 2.46, 95% CI, 1.83–3.31, P<0.001) and shorter DFS (HR 1.77, 95% CI, 1.08–2.89, P=0.02) compared to low CD68+ TAM density. A significant association was also found in the tumor nest. Analysis of CD163+ TAM density showed similar results (all P<0.001). Notably, the pooled analysis with multivariate-adjusted HRs for OS and DFS also found that a high TAM density was significantly related to poorer outcomes for BCa patients (all P<0.05). In addition, BCa patients with high TAM density were more likely to have larger tumors, no vascular invasion, and positive estrogen receptor expression (all P<0.05).Conclusion: This meta-analysis indicates that a high CD68+ and CD163+ TAM density is associated with poor OS and shorter DFS in BCa patients. Further clinical studies and in vivo experiments are needed to elucidate the underlying mechanism of TAMs.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022304853, identifier CRD42022304853.

Pancreatic cancer has an extremely terrible prognosis and is a common cause of cancer death. In this study, the clinic value, biological function and underlying mechanisms of Zinc finger protein 655 (ZNF655) in human pancreatic cancer were evaluated. The expression level of ZNF655 in pancreatic cancer was determined by immunohistochemistry (IHC) staining. The biological effects of ZNF655 in pancreatic cancer cells was investigated by loss/gain-of-function assays in vitro and in vivo. The downstream molecular mechanism of ZNF655 was explored using co-immunoprecipitation (Co-IP), dual-luciferase reporter and chromatin immunoprecipitation (Ch-IP). ZNF655 expression was significantly elevated in human pancreatic cancer and possessed clinical value in predicting poor prognosis. Functionally, ZNF655 knockdown inhibited the biological progression of pancreatic cancer cells, which was characterized by weaken proliferation, enhanced apoptosis, arrested cell cycle in G2, impeded migration, and suppressed tumor growth. Mechanistically, ZNF655 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the cyclin-dependent kinase 1 (CDK1) promoter. Furthermore, knockdown of CDK1 alleviated the promoting effects of ZNF655 overexpression in pancreatic cancer cells. The promotive role of ZNF655 in pancreatic cancer via CDK1 was determined, which drew further interest regarding its clinical application as a promising therapeutic target.