Cell and Bioscience最新文献

Background: Lactylation, a recently identified post-translational modification mediated by lactate, plays a critical role in regulating metabolic and immune processes in tumors. However, its function in neuroblastoma, particularly its association with tumor progression and immune modulation, remains unclear.

Method: We conducted immunohistochemical analyses on neuroblastoma tissue samples to evaluate lactylation levels and their clinical relevance. Single-cell RNA sequencing data and the AUCell algorithm were utilized to identify lactylation-related genes (LRGs) and map their expression within the tumor microenvironment. A seven-gene LRGs-based prognostic model was constructed using Cox regression and Least absolute shrinkage and selection operator (LASSO) analysis and validated in independent datasets. Bioinformatics analyses were performed to assess the associations between LRGs and clinical characteristics, biological pathways, immune infiltration, and therapeutic response. Functional assays further investigated the role of KLHL32, a key gene identified in the model.

Results: Our study revealed significantly elevated lactylation levels in neuroblastoma tumor tissues, which were associated with advanced disease stages and poor prognoses. We identified 407 LRGs and developed a seven-gene prognostic model that effectively stratified patients by risk, showing robust predictive performance in both internal and external validations. High-risk patients exhibited increased activation of tumor-promoting pathways, including glycolysis and PI3K/AKT signaling, alongside reduced immune cell infiltration, indicative of an immunosuppressive tumor microenvironment. Among the LRGs, KLHL32 emerged as a key tumor suppressor, inhibiting neuroblastoma cell proliferation, migration, and invasion, while enhancing NK cell-mediated cytotoxicity and anti-GD2 immunotherapies response. KLHL32 overexpression suppressed lactate production by downregulating the PI3K/AKT pathway, reducing protein lactylation levels, and promoting anti-tumor immunity.

Conclusion: Our findings establish lactylation as a critical determinant of neuroblastoma progression and prognosis. The seven-gene lactylation-related prognostic model provides a novel tool for patient stratification and therapeutic decision-making. Additionally, KLHL32 represents a promising target for enhancing immunotherapy efficacy by modulating metabolic and immune pathways, offering new opportunities for precision treatment in high-risk neuroblastoma patients.

Epigenetic regulation is crucial in directing T-cell differentiation, function, and fate, thereby influencing the success of T-cell-based immunotherapies. This review begins with an overview of the evolution of T-cell immunotherapies in cancer treatment. We then examine key epigenetic regulators-such as DNA methylation, mRNA methylation, and histone methylation-and their roles in shaping T-cell states during infection and tumorigenesis. The contributions of these regulators to T-cell exhaustion and lineage commitment are discussed in the context of immunotherapy efficacy. We highlight recent advances in targeting epigenetic pathways to enhance CAR-T and TCR-based therapies and conclude with current challenges and emerging strategies to improve the durability and effectiveness of adoptive T-cell therapies.

Background: Atherosclerosis (AS) serves as the pathological foundation for numerous cardiovascular and cerebrovascular diseases and is highly comorbid with depression. The mechanisms underlying this co-morbidity are exceptionally complex, posing significant challenges to effective clinical treatment. Consequently, our study aims to explore the potential biomarkers and mechanisms involved in developing atherosclerosis co-depression disease.

Methods: We performed differential expression analysis, protein-protein interaction analysis, Gene Ontology (GO) function enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on co-differentiated genes using AS and depression-related datasets from the GEO database. Potential biomarkers were identified through ROC curve analysis. To evaluate the effectiveness of the model, we established an animal model of AS comorbid with depressive disorder and performed a series of assessments, including the sugar-water preference test, open field test, tail suspension test, lipid profile analysis, and pathological examination of aortic sections. Additionally, RNA sequencing analysis of brain tissue, Golgi staining, and detection of synaptic function-related proteins were performed in AS comorbid depressed mice. Finally, in vitro cellular experiments were conducted to further validate the molecular targets and underlying mechanisms.

Results: We identified 968 differentially expressed genes associated with AS and 472 differentially expressed genes associated with depression, with 30 genes co-differentially expressed. Protein-protein interaction (PPI) analysis revealed that CCR5, CCR2, NPY, and OPRM1 were strongly associated with AS co-depression, while ROC analysis indicated that Shank2, MDGA2, and S100B were diagnostic markers for AS with depression. Differentially expressed genes were closely associated with the chemokine signaling pathway, neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, and taste transduction. Animal studies demonstrated that ApoE^-/- mice exhibited elevated lipids, atherosclerotic plaques, and depressive behaviors. RNA sequencing revealed that 30 genes were differentially expressed in the high-fat combined bind (HFB) group, with inflammatory pathways also activated in the brain. Shank2 expression was decreased in the hippocampus and prefrontal cortex, and Golgi staining revealed impaired synaptic plasticity. Cellular experiments demonstrated that IL-1β could induce a decrease in Shank2 expression.

Conclusion: Our study identified seven candidate AS co-depression biomarkers and verified that inflammation-induced damage to synaptic plastic rows is an important mechanism of AS co-depression, providing new insights into the diagnosis and treatment of AS co-depression disorders.

Background: GLP2R has been identified as a downregulated gene in colorectal cancer (CRC) and is correlated with immunocyte infiltration. Herein, we aimed to define the molecular characteristics of GLP2R in CRC, focusing on glycolysis and immune evasion.

Methods: CRC cells were infected with lentiviruses to analyze the impact of the genetic intervention on the malignant activity of tumor cells in vitro. Three animal models were developed, including an orthotopic tumor model, an experimental liver metastasis model, and an AOM/DSS-induced primary model. ChIP-qPCR and dual-luciferase assays were carried out to analyze the transcriptional regulation of GLP2R by MEOX1. MeDIP and MSP were used to reveal the effects of DNA methylation on MEOX1 expression.

Results: GLP2R expression was reduced in CRC and correlated with dismal prognosis for patients. Overexpression of GLP2R delayed the growth and metastasis of CRC cells and enhanced the activation of toxic CD4⁺ T cells and antigen-presenting DC cells. GLP2R knockout accelerated AOM/DSS-induced CRC in mice. GLP2R upregulation inhibited YAP1-mediated glycolysis in CRC cells by activating the Hippo signaling. Blocking Hippo signaling reversed the anti-tumor effects of GLP2R overexpression in vitro. MEOX1 promoted the GLP2R transcription by binding to its promoter, and MEOX1 inhibited the CRC growth and metastasis in a GLP2R-dependent manner. MEOX1 promoter DNA methylation was augmented in CRC tissues and cells, and MEOX1 expression was rescued by inhibiting DNA methylation.

Conclusions: DNA hypermethylation blocked MEOX1-mediated GLP2R transcription, which activated glycolysis in CRC cells by inhibiting Hippo signaling, leading to CRC growth, metastasis, and immune evasion.

Background: Resistance to chemotherapy drugs is one of the significant factors for limited treatment options and poor prognosis in esophageal cancer. A study has found that SOX12 plays a role in cisplatin resistance in hepatocellular carcinoma cells, but the function and mechanism of SOX12 in cisplatin resistance in esophageal cancer are unclear.

Results: Our study found that SOX12 protein levels are significantly elevated in cisplatin-resistant esophageal cancer cell lines and in esophageal cancer cells treated with cisplatin. Knocking down SOX12 enhances the sensitivity of esophageal cancer cells to cisplatin. Additionally, we have observed that elevated SOX12 protein promotes the efficiency of DNA double-strand break repair. Mechanistically, we found that the depletion of SOX12 results in a notable reduction in the levels of RNF168 protein, while its mRNA expression remains unaffected. Furthermore, we demonstrated that SOX12 regulates RNF168 protein stability by transcriptionally repressing the expression of TRIP12 and UBR5. On the other hand, we have also discovered that RNF168 interacts with and stabilizes SOX12 protein via a ubiquitin-proteasome system.

Conclusions: Collectively, our study identifies a feedback regulatory loop between SOX12 and RNF168 that promotes DNA damage repair and cisplatin resistance in esophageal cancer cells.

Aims/hypothesis: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally and is closely associated with type 2 diabetes (T2D) and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer partial therapeutic benefits in MASLD, but their efficacy is often limited in advanced insulin-resistant states, highlighting the need for adjunctive strategies to improve treatment responsiveness.

Methods: We investigated the metabolic and mechanistic effects of combining semaglutide (GLP-1RA) with Akkermansia muciniphila 11 (Akk11) in db/db mice, a model of T2D-associated MASLD. Mice were treated with semaglutide alone or in combination with Akk11. Metabolic parameters, hepatic and adipose tissue morphology, gut microbiota composition, transcriptomic profiles, and inflammatory signaling were evaluated.

Results: GLP-1RA monotherapy elicited only modest improvements in glycemia and hepatic lipid accumulation, with effects waning over time. However, Akk11 supplementation significantly enhanced semaglutide therapeutic effects, leading to reduced subcutaneous and visceral fat, improved liver histology, and decreased serum triglycerides. Mechanistically, combination treatment suppressed fatty acid synthesis, promoted mitochondrial function, and remodeled the gut microbiota. Notably, both GLP-1RA and AKK attenuated intestinal pyroptosis pathways, and the combination further suppressed pro-inflammatory markers in the liver and intestine.

Conclusions/interpretation: Our findings highlight a synergistic interaction between GLP-1RA and Akk11, likely mediated through microbiota remodeling and parallel improvements in lipid metabolism across intestinal, hepatic, and adipose compartments. This study supports the development of microbiota-guided strategies to enhance therapies for MASLD and other metabolic diseases.

Maternal hyperhomocysteinemia (HHcy) is closely linked to fetal growth restriction (FGR), yet the underlying mechanisms remain incompletely understood. In this study, we established a rat model of HHcy by administering a high-methionine diet during pregnancy and confirmed the presence of FGR through fetal weight analysis. Histological evaluation of the maternal-fetal interface revealed reduced vascular density in both the decidua and placenta, accompanied by dysregulated expression of key angiogenic factors in decidua. To elucidate the mechanistic basis of these changes, primary decidual stromal cells (DSCs) were isolated and RNA sequencing was performed. HHcy impaired the proangiogenic capacity of DSCs by suppressing vascular endothelial growth factor A (VEGFA) secretion. Transcriptomic profiling identified significant enrichment of lipid metabolism pathways in HHcy-exposed decidua. Further molecular analyses revealed that CD36 played a central role in mediating HHcy-induced lipid metabolic disturbances, which in turn activated the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Importantly, pharmacological inhibition of CD36 in DSCs alleviated lipid accumulation, suppressed PPAR pathway activation, and restored VEGFA expression and secretion, thereby rescuing DSCs-mediated angiogenesis. Collectively, our findings suggest that maternal HHcy upregulates CD36 expression in DSCs, leading to lipid metabolism dysregulation and impaired VEGFA-mediated angiogenesis possibly via the PPAR pathway, ultimately contributing to the pathogenesis of FGR. This is the first study to implicate lipid metabolism as a critical regulator of decidual angiogenesis, offering novel mechanistic insights and a potential therapeutic target for HHcy-associated pregnancy complications.

Background: Psoriasis and atopic dermatitis (AD) are two prevalent inflammatory skin disorders, each characterized by distinct adaptive immune responses. However, recent evidence suggests that these diseases may share overlapping immune mechanisms, especially concerning keratinocyte function. The specific cytokines that coordinate these inflammatory pathways remain largely undefined.

Methods: The expression of IL-27 and its receptor was analyzed using data derived from GEO datasets. Imiquimod-induced psoriasis-like and MC903-induced AD-like skin inflammation models were established in wild-type and Il27ra knockout littermates. Skin inflammation was evaluated using clinical scoring, histology, and immunostaining. Flow cytometry was employed to characterize immune cell populations in skin. Expression of relevant cytokines and signaling molecules was assessed using quantitative PCR, bulk RNA sequencing, and Western blotting.

Results: We found significantly elevated expression of the IL-27 receptor in the lesional skin of patients with psoriasis or AD. IL-27 receptor-deficient mice exhibited markedly reduced skin inflammation in both psoriasis-like and AD-like murine models. Mechanistic investigations revealed that IL-27 induces tumor necrosis factor-α production via signal transducer and activator of transcription 1 activation in keratinocytes, thereby potentiating inflammatory responses.

Conclusions: Our findings identify IL-27 signaling in keratinocytes as a pivotal regulator of skin inflammation in both psoriasis and AD. This highlights IL-27 as a promising therapeutic target for inflammatory skin diseases.