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.

Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a crucial signaling adaptor involved in multiple cellular events. However, its role in regulating osteoclastogenesis and energy metabolism remains unclear. Here, we report that TRAF1 promotes osteoclastogenesis and oxidative phosphorylation (OXPHOS). Employing RNA-sequencing, we found that TRAF1 is markedly upregulated during osteoclastogenesis and is positively associated with osteoporosis. TRAF1 knockout inhibits osteoclastogenesis and increases bone mass in both normal and ovariectomized adult mice, without affecting bone mass in childhood. Furthermore, TRAF1 promotes osteoclast OXPHOS by increasing the phosphorylation level of AKT. Mechanistically, TRAF1 functions to inhibit TRAF2-induced ubiquitination of Gβl, a known activator of AKT, and further upregulates AKT phosphorylation. Rescue experiments revealed that the inhibitory effects of TRAF1 knockout on osteoclastogenesis, OXPHOS, and bone mass are dependent on AKT. Collectively, our findings uncover a previously unrecognized function of TRAF1 in regulating osteoclastogenesis and energy metabolism, and establish a novel TRAF1-AKT-OXPHOS axis in osteoclasts.

Hematopoietic stem cells (HSC) maintain lifetime whole blood hematopoiesis through self-renewal and differentiation. In order to sustain HSC stemness, most HSC reside in a quiescence state, which is affected by diverse cellular stress and intracellular signal transduction. How HSC accommodate those challenges to preserve lifetime capacity remains elusive. Here we show that Pax transactivation domain-interacting protein (PTIP) is required for preserving HSC quiescence via regulating lysosomal activity. Using a genetic knockout mouse model to specifically delete Ptip in HSC, we find that loss of Ptip promotes HSC exiting quiescence, and results in functional exhaustion of HSC. Mechanistically, Ptip loss increases lysosomal degradative activity of HSC. Restraining lysosomal activity restores the quiescence and repopulation potency of Ptip-/- HSC. Additionally, PTIP interacts with SMAD2/3 and mediates transforming growth factor-β signaling-induced HSC quiescence. Overall, our work uncovers a key role of PTIP in sustaining HSC quiescence via regulating lysosomal activity.

Introduction: The causal relationship between type 1 diabetes mellitus (T1DM) and osteoporosis has not been clarified in large prospective cohort studies. This study aims to determine the causal link between T1DM and osteoporosis, and further identify eligible mediators.Material and methods: We explored the causal relationship between T1DM and osteoporosis by two-sample Mendelian randomization (MR), a method that uses genetic variants as instrumental variables for causal inference. We selected five candidate mediators based on their relevance to metabolic processes in T1DM and bone health, including body mass index (BMI), glycated hemoglobin (HbA1c), cholesterol in medium very low-density lipoprotein particles (M-VLDL-C), saturated fatty acids (SFA), and sex hormone-binding globulin (SHBG), and identified eligible mediators by two-step MR. We validated the correlation of T1DM and mediators with osteoporosis in a UK Biobank (UKB) prospective cohort study.Results: In MR analysis, T1DM was related to a significantly increased risk of osteoporosis (OR=1.046, 95% CI: 1.015 to 1.079, P=0.004). In two-step MR, T1DM was significantly associated with decreased levels of M-VLDL-C and SFA, increased levels of SHBG, but showed no significant effect on BMI or HbA1c. Furthermore, lower levels of M-VLDL-C and higher levels of SHBG, but not SFA, were significantly associated with an elevated risk of osteoporosis. Hence M-VLDL-C and SHBG were identified as eligible mediators. In UKB cohort study, consistent results were found.Conclusions: T1DM may cause osteoporosis by decreasing M-VLDL-C and increasing SHBG levels in plasma. The identified mediators may serve as important biomarkers for early detection and treatment of osteoporosis in T1DM patients.