Background: Diffuse large B-cell lymphoma (DLBCL), the most common type of Non-Hodgkin’s Lymphoma (NHL), has a lethal nature. Thus, the establishment of a novel model to predict the prognosis of DLBCL and guide its therapy is an urgency. Meanwhile, pyroptosis is engaged in the progression of DLBCL with further investigations required to reveal the underlying mechanism. Methods: LASSO regression was conducted to establish a risk model based on those PRGs. External datasets, RT-qPCR and IHC images from The Human Protein Alta (HPA) database were utilized to validate the model. ssGSEA was utilized to estimate the score of immune components in DLBCL. Results: A model based on 8 PRGs was established to generate a risk score. Validation of the model confirmed its robust performance. The risk score was associated with advanced clinical stages and shorter overall survivals. Two novel second-line chemotherapies were found to be potential treatments for high-risk patients. The risk score was also found to be correlated with immune components in DLBCL. Conclusion: This novel model can be utilized in clinical practices to predict the prognosis of DLBCL and guide the treatment of patients at high risk, providing an overview of immune regulatory program via pyroptosis in DLBCL.

Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis has been reported in various solid tumor models, its role in leukemogenesis remains elusive. Herein, we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance, suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia. Mechanistically, in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival, accompanied by the disruption of mitochondrial homeostasis. Interestingly, RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids (BCAAs), which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway. Additionally, the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2. More importantly, supplementation of BCAA enhanced the anti-tumor activity of genipin, a selective inhibitor that targets UCP2, resulting in significantly reduced acute myeloid leukemia blasts, increased mouse survival, and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.

Background: Diffuse large B-cell lymphoma (DLBCL), an aggressive subtype of non-Hodgkin lymphoma, exhibits heterogeneous clinical outcomes. While rituximab, a CD20 inhibitor, combined with chemotherapy has improved survival in some patients, resistance remains prevalent, particularly in hypoxic tumor microenvironments. Understanding hypoxia-related genes (HRGs) and their role in rituximab resistance is critical to addressing therapeutic challenges in high-risk DLBCL.Methods: Gene expression profiles from GEO datasets (GSE56315: DLBCL tumor vs. normal; GSE104212: hypoxia-treated DLBCL cell lines) were analyzed to identify overlapping genes between DLBCL-signature genes (DSGs) and HRGs. protein interaction network topology analysis and Lasso regression modeling of TCGA-DLBC dataset were employed to screen regulator and hub genes. Hub genes linked to rituximab response and survival were validated in DLBCL patients receiving rituximab therapy. Functional enrichment analysis was used to explore associated pathways. The expression of the identified regulator and hub genes was validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR).Results: 58 overlapping genes were identified between DSGs and HRGs. PPI network and Lasso regression revealed 5 MS4A1 regulator genes and 10 hub genes. Among these, LGALS1 (HR = 0.588, p = 0.00085), TIMP1 (HR = 0.591, p = 0.00098), ANXA1 (HR = 0.614, p=0.0024) and STAP1 (HR = 0.633, p=0.0035) were significantly associated with overall survival and GPNMB (AUC = 0.869), CDCA7 (AUC = 0.686), and STAP1 (AUC = 0.663) associated with treatment response in rituximab-treated patients. Functional analysis implicated these genes in B-cell receptor (BCR) and PI3K-AKT signaling pathways, suggesting their mechanistic roles in therapeutic resistance.Conclusions: This study identifies hypoxia-associated genes critical to rituximab resistance in DLBCL, highlighting potential therapeutic targets. Their involvement in BCR and PI3K-AKT pathways underscores novel vulnerabilities for overcoming refractory disease. Our findings provide a foundation for developing strategies to improve outcomes in high-risk DLBCL patients with hypoxic microenvironments.

Despite the dual roles of GALNT3 in various cellular processes in tumorigenesis of solid tumors, the clinical and biological significance of GALNT3 in lymp