A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis.

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

Turbulence of glutamine metabolism in pan-cancer prognosis and immune microenvironment.

Introduction: Glutamine is characterized as the nutrient required in tumor cells. The study based on glutamine metabolism aimed to develop a new predictive factor for pan-cancer prognostic and therapeutic analyses and to explore the mechanisms underlying the development of cancer. Methods: The RNA-sequence data retrieved from TCGA, ICGC, GEO, and CGGA databases were applied to train and further validate our signature. Single-cell RNA transcriptome data from GEO were used to investigate the correlation between glutamine metabolism and cell cycle progression. A series of bioinformatics and machine learning approaches were applied to accomplish the statistical analyses in this study. Results: As an individual risk factor, our signature could predict the overall survival (OS) and immunotherapy responses of patients in the pan-cancer analysis. The nomogram model combined several clinicopathological features, provided the GMscore, a readable measurement to clinically predict the probability of OS and improve the predictive capacity of GMscore. While analyzing the correlations between glutamine metabolism and malignant features of the tumor, we observed that the accumulation of TP53 inactivation might underlie glutamine metabolism with cell cycle progression in cancer. Supposedly, CAD and its upstream genes in glutamine metabolism would be potential targets in the therapy of patients with IDH-mutated glioma. Immune infiltration and sensitivity to anti-cancer drugs have been confirmed in the high-risk group. Discussion: In summary, glutamine metabolism is significant to the clinical outcomes of patients with pan-cancer and is tightly associated with several hallmarks of a malignant tumor.

Uncovering BTB and CNC Homology1 (BACH1) as a Novel Cancer Therapeutic Target.

BTB and CNC homology1 (BACH1), working as a transcriptional factor, is demonstrated to function on the regulation of epigenetic modifications by complex regulatory networks. Although BACH1 is reported as an oncogene, the overall analysis of its role remains lacking. In this study, we uncovered the capacity of BACH1 as a new pan-cancer therapeutic target. We found that BACH1 is highly expressed in abundant cancers and correlated with the poor prognosis of most cancers. The mutation sites of BACH1 varied in different cancer types and correlated to patients' prognoses. The tumor mutation burden (TMB) in four cancer species and up to six tumor infiltrated immune cells had a significant relevance with BACH1. The enrichment analysis showed that the BACH1-associated genes were significantly enriched in the pathways of PD-1/L1 expression, ubiquitin-mediated proteolysis, T cell receptor, Th17 cell differentiation. We then demonstrated that BACH1 is positively correlated with the expression of many candidate genes, incluing SRPK2, GCLM, SLC40A1, and HK2 but negatively correlated with the expression of KEAP1 and GAPDH. Overall, our data shed light on BACH1's effect on latent utility in cancer targeting therapy.

Tumor-Educated Platelets Facilitate Thrombus Formation Through Migration.

Platelets are small anucleate cells that circulate in the blood and form thrombi. Tumor-educated platelets are the platelets derived from cancer patients. Although many have reported that tumor-educated platelets are associated with cancer-associated thrombosis, their function in this process is poorly understood. Here we first collect the clinical data from 100 different cancer patients, showing that cancer patients are in a hypercoagulable state. Our experiment shows that tumor-educated platelets from melanoma-burdened mouse models can migrate faster and longer, forming more clots (thrombus). However, the plasma from tumor mice can inhibit platelet migration. The RNA sequence profile of tumor-educated platelets shows that many genes associated with cell migration and cell skeleton expressed significantly higher. Our research offers a new insight into the tumor-educated platelets to better understand the thrombus formation.