Metabolism-related Gene Signature Research Articles

A novel hypoxia- and lactate metabolism-related prognostic signature to characterize the immune landscape and predict immunotherapy response in osteosarcoma

BackgroundImmunotherapy has shown considerable promise in cancer treatment, yet only a minority of osteosarcoma patients derive benefits from this approach. Hypoxia and lactate metabolism are two predominant characteristics of the tumor microenvironment. These features are crucial for molding the immune landscape and thus have the potential to act as predictive indicators for immunotherapy response.MethodsPrognostic modeled genes were identified through univariate and multivariate Cox regression as well as LASSO regression analyses. The tumor microenvironment was evaluated using ESTIMATE, CIBERSORT, and ImmuCellAI analyses. Tide prediction and expression of immune checkpoints, MHC molecules, chemokines, interleukins, interferons, receptors, and other cytokines were utilized to estimate immunotherapy efficacy. Single-cell analysis was performed to demonstrate the expression of modeled genes among various immune cell types. Experimental validation was carried out to verify the expression and functions of SFXN4 and SQOR.ResultsA potent signature was constructed with 8 genes related to hypoxia and lactate metabolism, including MAFF, COL5A2, FAM162A, SQOR, UQCRB, SFXN4, PFKFB2 and COX6A2. A nomogram incorporating risk scores and other clinical features demonstrated excellent predictive capacity. Osteosarcoma patients with high-risk scores exhibited poor prognosis and more “cold” tumor characteristics. According to the ESTIMATE algorithm, these patients displayed lower immune, stromal, and ESTIMATE scores, partially attributed to inadequate infiltration of key immunocytes. The Ciborsort analysis similarly indicated that high-risk individuals had diminished infiltration of critical anti-tumor immune cells such as Cytotoxic T cells, CD4+ T cells, and NK cells. The low expression levels of certain immune checkpoints, MHC molecules, chemokines, interleukins, interferons, receptors, and other cytokines in high-risk cases suggested their unsatisfactory responses to immune treatment. Tide prediction further demonstrated that fewer individuals classified as high risk may exhibit sensitivity to immune checkpoint inhibitor therapy. Notably, SFXN4 was found to be highly expressed in osteosarcoma tissues and cells; it promoted the growth, migration, and invasion of osteosarcoma cells, while SQOR had the opposite effect.ConclusionOur research has developed a robust hypoxia- and lactate metabolism-related gene signature, providing a solid theoretical foundation for prognosis prediction, classification of “cold” and “hot” tumors, accessing immunotherapy response, and directing personalized treatment for osteosarcoma.

A lactate metabolism-related gene signature to diagnose osteoarthritis based on machine learning combined with experimental validation.

Lactate is gradually proved as the essential regulator in intercellular signal transduction, energy metabolism reprogramming, and histone modification. This study aims to clarify the diagnosis value of lactate metabolism-related genes in osteoarthritis (OA). Lactate metabolism-related genes were retrieved from the MSigDB. GSE51588 was downloaded from the Gene Expression Omnibus (GEO) as the training dataset. GSE114007, GSE117999, and GSE82107 datasets were adopted for external validation. Genomic difference detection, protein-protein interaction network analysis, LASSO, SVM-RFE, Boruta, and univariate logistic regression (LR) analyses were used for feature selection. Multivariate LR, Random Forest (RF), Support Vector Machine (SVM), and XGBoost (XGB) were used to develop the multiple-gene diagnosis models. 12 control and 12 OA samples were collected from the local hospital for re-verification. The transfection assays were conducted to explore the regulatory ability of the gene to the apoptosis and vitality of chondrocytes. Through the bioinformatical analyses and machine learning algorithms, SLC2A1 and NDUFB9 of the 273 lactate metabolism-related genes were identified as the significant diagnosis biomarkers. The LR, RF, SVM, and XGB models performed impressively in the cohorts (AUC > 0.7). The local clinical samples indicated that SLC2A1 and NDUFB9 were both down-regulated in the OA samples (both P < 0.05). The knockdown of NDUFB9 inhibited the viability and promoted the apoptosis of the CHON-001 cells treated with IL-1beta (both P < 0.05). A lactate metabolism-related gene signature was constructed to diagnose OA, which was validated in multiple independent cohorts, local clinical samples, and cellular functional experiments.

Identification of prognostic biomarkers related to retinoic acid metabolism in gliomas and analysis of their impact on the immune microenvironment.

Glioma is a primary tumor of the central nervous system. Numerous investigations have demonstrated that retinoic acid (RA) signaling plays an important role in glioblastoma. This research aimed to develop a RA metabolism-related gene signature associated with glioma. The RA metabolism-related differentially expressed genes were obtained through differential analysis of RA metabolism-related genes in GSE4290. The univariate Cox and least absolute shrinkage and selection operator regression analysis were adopted to build a RA metabolism-related glioma prognostic signature. We further conducted immune feature estimation and functional enrichment analysis between 2 risk subgroups. Finally, the potential drug-targeting prognostic genes were predicted through the DrugBank database. A sum of 10 RA metabolism-related differentially expressed genes between normal and tumor groups were identified. Then, a RA metabolism-related prognostic signature was built based on the 7 prognostic genes (ADH4, DHRS3, DHRS9, LRAT, RDH10, RDH12, and RDH5). Glioma patients were separated into 2 risk subgroups (low-risk vs high-risk) based on the median value of the risk score. We found that monocytes were negatively correlated with DHRS9, while activated naive CD4+T cell was positively correlated with RDH10. These prognostic genes participated in some immune-related processes, such as "B cell-mediated immunity." Finally, 4 drugs targeting DHRS3, LRAT, and RDH12 were predicted, including vitamin A, nicotinamide adenine dinucleotide, ethanol, and cyclohexylformamide. The prognostic signature comprised of ADH4, DHRS3, DHRS9, LRAT, RDH10, RDH12, and RDH5 based on RA metabolism was established, which provided a theoretical basis and reference value for the research of glioma.

Integrated analysis reveals an aspartate metabolism-related gene signature for predicting the overall survival in patients with hepatocellular carcinoma.

Deregulating cellular metabolism is one of the prominent hallmarks of malignancy, with a critical role in tumor survival and growth. However, the role of reprogramming aspartate metabolism in hepatocellular carcinoma (HCC) are largely unknown. The multi-omics data of HCC patients were downloaded from public databases. Univariate and multivariate stepwise Cox regression were used to establish an aspartate metabolism-related gene signature (AMGS) in HCC. The Kaplan-Meier and receiver operating characteristic curve analyses were performed to evaluate the predictive ability for overall survival (OS) in HCC patients. Gene set enrichment analysis and immune infiltration analysis were operated to determine the potential mechanisms underlying the AMGS. Single-cell RNA sequencing (scRNA-seq) data of liver cancer stem cells were visualized by t-SNE algorithm. In vivo and in vitro experiments were implemented to investigate the biological function of CAD in HCC. In addition, a nomogram based on the AMGS and clinicopathologic characteristics was constructed by univariate and multivariate Cox regression analyses. Patients in the high-AMGS subgroup exerted advanced tumor status and poor prognosis. Mechanistically, the high-AMGS subgroup patients had significantly enhanced proliferation and stemness-related pathways, increased infiltration of regulatory T cells and upregulated expression levels of suppressive immune checkpoints in the tumor immune microenvironment. Notably, scRNA-seq data revealed CAD, one of the aspartate metabolism-related gene, is significantly upregulated in liver cancer stem cells. Silencing CAD inhibited proliferative capacity and stemness properties of HCC cells in vitro and in vivo. Finally, a novel nomogram based on the AMGS showed an accurate prediction in HCC patients. The AMGS represents a promising prognostic value for HCC patients, providing a perspective for finding novel biomarkers and therapeutic targets for HCC.

Copper metabolism–related signature for prognosis prediction and MMP13 served as malignant factor for breast cancer

ObjectivesTo comprehensively analyze the copper metabolism in Breast cancer, we established a prognostic signature for breast cancer (BC) related to copper metabolism. MethodsCopper metabolism-related genes were sourced from previous literatures and were selected by the Univariate Cox regression. Cu-enrichment scores were calculated via ssGSEA. Differentially expressed genes were identified with limma between high and low Cu-enrichment scores group, then we used the Random Survival Forest and LASSO to build the CuScore for BC. Kaplan-Meier analysis, ROC curves, and Cox regression were used to evaluate CuScore. Genomic mutations were analyzed with GISTIC. Immune cells were examined using ESTIMATE, ssGSEA and TIMER. Enrichment analysis used clusterProfiler and GSVA. The GDSC database and oncoPredict package analyzed chemotherapeutic sensitivity. MMP13 was selected for in vitro assays. ResultsFour copper metabolism-related genes (UBE2D2, SLC31A1, ATP7A, and MAPK1) with prognostic value were identified. Higher expression levels of these genes were associated with higher Cu-enrichment scores, a factor of malignancy in breast cancer. Among 115 differentially expressed genes, 19 prognostic genes were identified, with three (CEACAM5, MMP13, and CRISP3) highlighted by Random Survival Forest and LASSO. Higher CuScores correlated with worse prognoses and were effective in predicting breast cancer outcomes. CuScore and metastasis were independent prognostic factors. Tumor-infiltrating immune cells were associated with lower CuScores. GO-GSEA analysis indicated six immune-related pathways might be regulated by CuScore. Patients with higher CuScores had lower TMB and were more sensitive to Sapitinib and LCL161, while those with lower CuScores might respond better to anti-PD1 therapy. High MMP13 expression in breast cancer was linked to malignancy, affecting cell proliferation and migration. ConclusionThe identified copper metabolism-related gene signature has the potential to predict prognosis and guide clinical treatment for BC. Among these genes, MMP13 may act as a malignant factor in BC.

A novel amino acid metabolism-related gene signature to predict the overall survival of esophageal squamous cell carcinoma patients.

Esophageal squamous cell carcinoma (ESCC) has a poor early detection rate, prognosis, and survival rate. Effective prognostic markers are urgently needed to assist in the prediction of ESCC treatment outcomes. There is accumulating evidence of a strong relationship between cancer cell growth and amino acid metabolism. This study aims to determine the relationship between amino acid metabolism and ESCC prognosis. This study comprehensively evaluates the association between amino acid metabolism-related gene (AAMRG) expression profiles and the prognosis of ESCC patients based on data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify the expression of prognosis-related genes. A univariate Cox regression analysis of TCGA data identified 18 prognosis-related AAMRGs. The gene expression profiles of 90 ESCC tumor and normal tissues were obtained from the GSE20347 and GSE67269 datasets. Two differently expressed genes (DEGs) were considered as ESCC prognosis-related genes; and they were branched-chain amino acid transaminase 1 (BCAT1) and methylmalonic aciduria and homocystinuria type C protein (MMACHC). These two AAMRGs were used to develop a novel AAMRG-related gene signature to predict 1- and 2-year prognostic risk in ESCC patients. Both BCAT1 and MMACHC expression were verified by RT-qPCR. A prognostic nomogram that incorporated clinical factors and BCAT1 and MMACHC gene expression was constructed, and the calibration plots showed that it had good prognostic performance. The AAMRG signature established in our study is efficient and could be used in clinical settings to predict the early prognosis of ESCC patients.

Identification of lipid metabolism-related gene signature in the bone marrow microenvironment of multiple myelomas through deep analysis of transcriptomic data

Dysregulated lipid metabolism in the bone marrow microenvironment (BMM) plays a vital role in multiple myeloma (MM) development, progression, and drug resistance. However, the exact mechanism by which lipid metabolism impacts the BMM, promotes tumorigenesis, and triggers drug resistance remains to be fully elucidated.By analyzing the bulk sequencing and single-cell sequencing data of MM patients, we identified lipid metabolism-related genes differential expression significantly associated with MM prognosis, referred to as LMRPgenes. Using a cohort of ten machine learning algorithms and 117 combinations, LMRPgenes predictive models were constructed. Further exploration of the effects of the model risk score (RS) on the survival status, immune status of patients with BMM, and response to immunotherapy was conducted. The study also facilitated the identification of personalized therapeutic strategies targeting specified risk categories within patient cohorts.Analysis of the scRNA-seq data revealed increased lipid metabolism-related gene enrichment scores (LMESs) in erythroblasts and progenitor, malignant, and Tprolif cells but decreased LMESs in lymphocytes. LMESs were also strongly correlated with most of the 50 hallmark pathways within these cell populations. An elevated malignant cell ratio and reduced lymphocytes were observed in the high LMES group. Moreover, the LMRPgenes predictive model, consisting of 14 genes, showed great predictive power. The risk score emerged as an independent indicator of poor outcomes. Inverse relationships between the RS and immune status were noted, and a high RS was associated with impaired immunotherapy responses. Drug sensitivity assays indicated the effectiveness of bortezomib, buparlisib, dinaciclib, staurosporine, rapamycin, and MST-312 in the high-RS group, suggesting their potential for treating patients with high-RS values and poor response to immunotherapy. Ultimately, upon verification via qRT-PCR, we observed a significant upregulation of ACBD6 in NDMM group compared to the control group.Our research enhances the knowledge base regarding the association between lipid metabolism-related genes (LMRGs) and the BMM in MM patients, offering substantive insights into the mechanistic effects of the BMM mediated by LMRGs.Graphical abstract

Immune- and metabolism-related gene signature analysis uncovers the prognostic and immune microenvironments of hepatocellular carcinoma

BackgroundMetabolic reprogramming is an emerging hallmark that influences the tumour microenvironment (TME) by regulating the behavior of cancer cells and immune cells. The relationship between metabolism and immunity remains elusive. The purpose of this study was to explore the predictive value of immune- and metabolism-related genes in hepatocellular carcinoma (HCC) and their intricate interplay with TME.MethodsWe established the immune- and metabolism-related signature (IMRPS) based on the LIHC cohort from The Cancer Genome Atlas (TCGA) dataset. Kaplan–Meier analysis, receiver operating characteristic (ROC) curve analysis and Cox regression analysis confirmed the prognostic value of IMRPS. We investigated differences in immune cell infiltration, clinical features, and therapeutic response between risk groups. The quantitative real-time PCR (qPCR) was used to confirm the expression of signature genes. Immunohistochemical staining was performed to evaluate immune infiltration features in HCC tissue samples. We conducted cell experiments including gene knockout, cell counting kit-8 (CCK-8), and flow cytometry to explore the role of the IMRPS key gene UCK2 in HCC. RNA-seq was used to further investigate the potential underlying mechanism involved.ResultsThe IMRPS, composed of four genes, SMS, UCK2, PFKFB4 and MAPT, exhibited significant correlations with survival, immune cell infiltration, clinical features, immune checkpoints and therapeutic response. The IMRPS was shown to be an excellent predictor of HCC prognosis. It could stratify patients appropriately and characterize the TME accurately. The high-risk HCC group exhibited an immunosuppressive microenvironment with abundant M2-like macrophage infiltration, which was confirmed by the immunohistochemistry results. The results of qPCR revealed that the expression of signature genes in 20 HCC tissues was significantly greater than that in adjacent normal tissues. After the key gene UCK2 was knocked out, the proliferation of the Huh7 cell line was significantly inhibited, and monocyte-derived macrophages polarized towards an M1-like phenotype in the coculture system. RNA-seq and GSEA suggested that the phenotypes were closely related to the negative regulation of growth and regulation of macrophage chemotaxis.ConclusionsThis study established a new IMRS for the accurate prediction of patient prognosis and the TME, which is also helpful for identifying new targets for the treatment of HCC.

A novel mitochondrial metabolism-related gene signature for predicting the prognosis of oesophageal squamous cell carcinoma.

Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide. Due to the important role of mitochondrial metabolism in cancer progression, a clinical prognostic model based on mitochondrial metabolism and clinical features was constructed in this study to predict the prognosis of ESCC. Firstly, the mitochondrial metabolism scores (MMs) were calculated based on 152 mitochondrial metabolism-related genes (MMRGs) by single sample gene set enrichment analysis (ssGSEA). Subsequently, univariate Cox regression and LASSO algorithm were used to identify prognosis-associated MMRG and risk-stratify patients. Functional enrichment, interaction network and immune-related analyses were performed to explore the features differences in patients at different risks. Finally, a prognostic nomogram incorporating clinical factors was constructed to assess the prognosis of ESCC. Our results found there were differences in clinical features between the MMs-high group and the MMs-low group in the TCGA-ESCC dataset (P<0.05). Afterwards, we identified 6 MMRGs (COX10, ACADVL, IDH3B, AKR1A1, LIAS, and NDUFB8) signature that could accurately distinguish high-risk and low-risk ESCC patients. A predictive nomogram that combined the 6 MMRGs with sex and N stage to predict the prognosis of ESCC was constructed, and the areas under the receiver operating characteristic (ROC) curve at 1, 2 and 3 years were 0.948, 0.927 and 0.848, respectively. Finally, we found that COX10, one of 6 MMRGs, could inhibit the malignant progression of ESCC in vitro. In summary, we constructed a clinical prognosis model based on 6 MMRGs and clinical features which can accurately predict the prognosis of ESCC patients.

Glutathione metabolism-related gene signature predicts prognosis and treatment response in low-grade glioma.

Cancer cells can induce molecular changes that reshape cellular metabolism, creating specific vulnerabilities for targeted therapeutic interventions. Given the importance of reactive oxygen species (ROS) in tumor development and drug resistance, and the abundance of reduced glutathione (GSH) as the primary cellular antioxidant, we examined an integrated panel of 56 glutathione metabolism-related genes (GMRGs) across diverse cancer types. This analysis revealed a remarkable association between GMRGs and low-grade glioma (LGG) survival. Unsupervised clustering and a GMRGs-based risk score (GS) categorized LGG patients into two groups, linking elevated glutathione metabolism to poorer prognosis and treatment outcomes. Our GS model outperformed established clinical prognostic factors, acting as an independent prognostic factor. GS also exhibited correlations with pro-tumor M2 macrophage infiltration, upregulated immunosuppressive genes, and diminished responses to various cancer therapies. Experimental validation in glioma cell lines confirmed the critical role of glutathione metabolism in glioma cell proliferation and chemoresistance. Our findings highlight the presence of a unique metabolic susceptibility in LGG and introduce a novel GS system as a highly effective tool for predicting the prognosis of LGG.

Identification of a fatty acid metabolism-related gene signature to predict prognosis in stomach adenocarcinoma.

Fatty acid metabolism (FAM) contributes to tumorigenesis and tumor development, but the role of FAM in the progression of stomach adenocarcinoma (STAD) has not been comprehensively clarified. The expression data and clinical follow-up information were obtained from The Cancer Genome Atlas (TCGA). FAM pathway was analyzed by gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) methods. Univariate Cox regression analysis was conducted to select prognosis genes. Molecular subtypes were classified by consensus clustering analysis. Furthermore, least absolute shrinkage and selection operator (Lasso) analysis was employed to develop a risk model. ESTIMATE and tumour immune dysfunction and exclusion (TIDE) algorithm were used to assess immunity. pRRophetic package was conducted to predict drug sensitivity. Based on 14 FAM related prognosis genes (FAMRG), 2 clusters were determined. Patients in C2 showed a worse overall survival (OS). Furthermore, a 7-FAMRG risk model was established as an independent predictor for STAD, with a higher riskscore indicating an unfavorable OS. High riskscore patients had higher TIDE score and these patients were more sensitive to anticancer drugs such as Bortezomib, Dasatinib and Pazopanib. A nomogram based on riskscore was an effective prediction tool applicable to clinical settings. The results from pan-cancer analysis supported a prominent application value of riskscore model in other cancer types. The FAMRGs model established in this study could help predict STAD prognosis and offer new directions for future studies on dysfunctional FAM-induced damage and anti-tumor drugs in STAD disease.

Construction and validation of a folate metabolism-related gene signature for predicting prognosis in HNSCC

PurposeMetabolic reprogramming is currently considered a hallmark of tumor and immune development. It is obviously of interest to identify metabolic enzymes that are associated with clinical prognosis in head and neck squamous cell carcinomas (HNSCC).MethodsCandidate genes were screened to construct folate metabolism scores by Cox regression analysis. Functional enrichment between high- and low-folate metabolism groups was explored by GO, KEGG, GSVA, and ssGSEA. EPIC, MCPcounter, and xCell were utilized to explore immune cell infiltration between high- and low-folate metabolism groups. Relevant metabolic scores were calculated and visually analyzed by the “IOBR” software package.ResultsTo investigate the mechanism behind metabolic reprogramming of HNSCC, 2886 human genes associated with 86 metabolic pathways were selected. Folate metabolism is significantly enriched in HNSCC, and that the six-gene (MTHFD1L, MTHFD2, SHMT2, ATIC, MTFMT, and MTHFS) folate score accurately predicts and differentiates folate metabolism levels. Reprogramming of folate metabolism affects CD8T cell infiltration and induces immune escape through the MIF signaling pathway. Further research found that SHMT2, an enzyme involved in folate metabolism, inhibits CD8T cell infiltration and induces immune escape by regulating the MIF/CD44 signaling axis, which in turn promotes HNSCC progression.ConclusionsOur study identified a novel and robust folate metabolic signature. A folate metabolic signature comprising six genes was effective in assessing the prognosis and reflecting the immune status of HNSCC patients. The target molecule of folate metabolic reprogramming, SHMT2, probably plays a very important role in HNSCC development and immune escape.

Integrating iron metabolism-related gene signature to evaluate prognosis and immune infiltration in nasopharyngeal carcinoma

BackgroundDysregulation of iron metabolism has been shown to have significant implications for cancer development. We aimed to investigate the prognostic and immunological significance of iron metabolism-related genes (IMRGs) in nasopharyngeal carcinoma (NPC).MethodsMultiple Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were analyzed to identify key IMRGs associated with prognosis. Additionally, the immunological significance of IMRGs was explored.ResultsA novel risk model was established using the LASSO regression algorithm, incorporating three genes (TFRC, SLC39A14, and ATP6V0D1).This model categorized patients into low and high-risk groups, and Kaplan–Meier analysis revealed significantly shorter progression-free survival for the high-risk group (P < 0.0001). The prognostic model’s accuracy was additionally confirmed by employing time-dependent Receiver Operating Characteristic (ROC) curves and conducting Decision Curve Analysis (DCA). High-risk patients were found to correlate with advanced clinical stages, specific tumor microenvironment subtypes, and distinct morphologies. ESTIMATE analysis demonstrated a significant inverse relationship between increased immune, stromal, and ESTIMATE scores and lowered risk score. Immune analysis indicated a negative correlation between high-risk score and the abundance of most tumor-infiltrating immune cells, including dendritic cells, CD8+ T cells, CD4+ T cells, and B cells. This correlation extended to immune checkpoint genes such as PDCD1, CTLA4, TIGIT, LAG3, and BTLA. The protein expression patterns of selected genes in clinical NPC samples were validated through immunohistochemistry.ConclusionThis study presents a prognostic model utilizing IMRGs in NPC, which could assist in assessing patient prognosis and provide insights into new therapeutic targets for NPC.

Development and experimental validation of an energy metabolism-related gene signature for diagnosing of osteoporosis

Osteoporosis is usually caused by excessive bone resorption and energy metabolism plays a critical role in the development of osteoporosis. However, little is known about the role of energy metabolism-related genes in osteoporosis. This study aimed to explore the important energy metabolism-related genes involved in the development of osteoporosis and develop a diagnosis signature for osteoporosis. The GSE56814, GSE62402, and GSE7158 datasets were downloaded from the NCBI Gene Expression Omnibus. The intersection of differentially expressed genes between high and low levels of body mineral density (BMD) and genes related to energy metabolism were screened as differentially expressed energy metabolism genes (DE-EMGs). Subsequently, a DE-EMG-based diagnostic model was constructed and differential expression of genes in the model was validated by RT-qPCR. Furthermore, a receiver operating characteristic curve and nomogram model were constructed to evaluate the predictive ability of the diagnostic model. Finally, the immune cell types in the merged samples and networks associated with the selected optimal DE-EMGs were constructed. A total of 72 overlapped genes were selected as DE-EMGs, and a five DE-EMG based diagnostic model consisting B4GALT4, ADH4, ACAD11, B4GALT2, and PPP1R3C was established. The areas under the curve of the five genes in the merged training dataset and B4GALT2 in the validation dataset were 0.784 and 0.790, respectively. Moreover, good prognostic prediction ability was observed using the nomogram model (C index = 0.9201; P = 5.507e−14). Significant differences were observed in five immune cell types between the high- and low-BMD groups. These included central memory, effector memory, and activated CD8 T cells, as well as regulatory T cells and activated B cells. A network related to DE-EMGs was constructed, including hsa-miR-23b-3p, DANCR, 17 small-molecule drugs, and two Kyoto Encyclopedia of Genes and Genomes pathways, including metabolic pathways and pyruvate metabolism. Our findings highlighted the important roles of DE-EMGs in the development of osteoporosis. Furthermore, the DANCR/hsa-miR-23b-3p/B4GALT4 axis might provide novel molecular insights into the process of osteoporosis development.

Identification of fatty acids synthesis and metabolism-related gene signature and prediction of prognostic model in hepatocellular carcinoma.

Fatty acids synthesis and metabolism (FASM)-driven lipid mobilization is essential for energy production during nutrient shortages. However, the molecular characteristics, physiological function and clinical prognosis value of FASM-associated gene signatures in hepatocellular carcinoma (HCC) remain elusive. The Gene Expression Omnibus database (GEO), the Cancer Genome Atlas (TCGA), and International Cancer Genome Consortium (ICGC) database were utilized to acquire transcriptome data and clinical information of HCC patients. The ConsensusClusterPlus was employed for unsupervised clustering. Subsequently, immune cell infiltration, stemness index and therapeutic response among distinct clusters were decoded. The tumor immune dysfunction and exclusion (TIDE) algorithm was utilized to anticipate the response of patients towards immunotherapy, and the genomics of drug sensitivity in cancer (GDSC) tool was employed to predict their response to antineoplastic medications. Least absolute shrinkage and selection operator (LASSO) regression analysis and protein-protein interaction (PPI) network were employed to construct prognostic model and identity hub gene. Single cell RNA sequencing (scRNA-seq) and CellChat were used to analyze cellular interactions. The hub gene of FASM effect on promoting tumor progression was confirmed through a series of functional experiments. Twenty-six FASM-related genes showed differential expression in HCC. Based on these FASM-related differential genes, two molecular subtypes were established, including Cluster1 and Cluster2 subtype. Compared with cluster2, Cluster1 subtype exhibited a worse prognosis, higher risk, higher immunosuppressive cells infiltrations, higher immune escape, higher cancer stemness and enhanced treatment-resistant. PPI network identified Acetyl-CoA carboxylase1 (ACACA) as central gene of FASM and predicted a poor prognosis. A strong interaction between cancer stem cells (CSCs) with high expression of ACACA and macrophages through CD74 molecule (CD74) and integrin subunit beta 1 (ITGB1) signaling was identified. Finally, increased ACACA expression was observed in HCC cells and patients, whereas depleted ACACA inhibited the stemness straits and drug resistance of HCC cells. This study provides a resource for understanding FASM heterogeneity in HCC. Evaluating the FASM patterns can help predict the prognosis and provide new insights into treatment response in HCC patients.

Identification and validation of a metabolism-related gene signature for predicting the prognosis of paediatric medulloblastoma

Medulloblastoma (MB) is a malignant brain tumour that is highly common in children and has a tendency to spread to the brain and spinal cord. MB is thought to be a metabolically driven brain tumour. Understanding tumour cell metabolic patterns and characteristics can provide a promising foundation for understanding MB pathogenesis and developing treatments. Here, by analysing RNA-seq data of MB samples from the Gene Expression Omnibus (GEO) database, 12 differentially expressed metabolic-related genes (DE-MRGs) were chosen for the construction of a predictive risk score model for MB. This model demonstrated outstanding accuracy in predicting the outcomes of MB patients and served as a standalone predictor. An evaluation of functional enrichment revealed that the risk score showed enrichment in pathways related to cancer promotion and the immune response. In addition, a high risk score was an independent poor prognostic factor for MB in patients with different ages, sexes, metastasis stages and subgroups (SHH and Group 4). Consistently, the metabolic enzyme ornithine decarboxylase (ODC1) was upregulated in MB patients with poor survival time. Inhibition of ODC1 in primary and metastatic MB cell lines decreased cell proliferation, migration and invasion but increased immune infiltration. This study could aid in identifying metabolic targets for MB as well as optimizing risk stratification systems and individual treatment plans for MB patients via the use of a metabolism-related gene prognostic risk score signature.

Mitochondrial energy metabolism-related gene signature as a prognostic indicator for pancreatic adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant gastrointestinal tumor and is associated with an unfavorable prognosis worldwide. Considering the effect of mitochondrial metabolism on the prognosis of pancreatic cancer has rarely been investigated, we aimed to establish prognostic gene markers associated with mitochondrial energy metabolism for the prediction of survival probability in patients with PAAD. Methods: Gene expression data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases, and the mitochondrial energy metabolism-related genes were obtained from the GeneCards database. Based on mitochondrial energy metabolism score (MMs), differentially expressed MMRGs were established for MMs-high and MMs-low groups using ssGSEA. After the univariate Cox and least absolute and selection operator (LASSO) analyses, a prognostic MMRG signature was used in the multivariate Cox proportional regression model. Survival and immune cell infiltration analyses were performed. In addition, a nomogram based on the risk model was used to predict the survival probability of patients with PAAD. Finally, the expression of key genes was verified using quantitative polymerase chain reaction and immunohistochemical staining. Intro cell experiments were performed to evaluated the proliferation and invasion of pancreatic cancer cells. Results: A prognostic signature was constructed consisting of two mitochondrial energy metabolism-related genes (MMP11, COL10A1). Calibration and receiver operating characteristic (ROC) curves verified the good predictability performance of the risk model for the survival rate of patients with PAAD. Finally, immune-related analysis explained the differences in immune status between the two subgroups based on the risk model. The high-risk score group showed higher estimate, immune, and stromal scores, expression of eight checkpoint genes, and infiltration of M0 macrophages, which might indicate a beneficial response to immunotherapy. The qPCR results confirmed high expression of MMP11 in pancreatic cancer cell lines, and IHC also verified high expression of MMP11 in clinical pancreatic ductal adenocarcinoma tissues. In vitro cell experiments also demonstrated the role of MMP11 in cell proliferation and invasion. Conclusion: Our study provides a novel two-prognostic gene signature-based on MMRGs-that accurately predicted the survival of patients with PAAD and could be used for mitochondrial energy metabolism-related therapies in the future.

Identification of sulfur metabolism-related gene signature in osteoarthritis and TM9SF2’s sustenance effect on M2 macrophages' phagocytic activity

BackgroundOsteoarthritis (OA) is a chronic and low-grade inflammatory disease associated with metabolism disorder and multiple cell death types in the synovial tissues. Sulfur metabolism has not been studied in OA.MethodsFirst, we calculated the single sample gene set enrichment analysis score of sulfur metabolism-associated annotations (i.e., cysteine metabolism process, regulation of sulfur metabolism process, and disulfidptosis) between healthy and synovial samples from patients with OA. Sulfur metabolism-related differentially expressed genes (DEGs) were analyzed in OA. Least absolute shrinkage and selection operator COX regression were used to identify the sulfur metabolism-associated gene signature for diagnosing OA. Correlation and immune cell deconvolution analyses were used to explore the correlated functions and cell specificity of the signature gene, TM9SF2. TM9SF2’s effect on the phagocytosis of macrophages M2 was analyzed by coculturing macrophages with IgG-coated beads or apoptotic Jurkat cells.ResultsA diagnostic six gene signature (i.e., MTHFD1, PDK4, TM9SF2, POU4F1, HOXA2, NCKAP1) was identified based on the ten DEGs, validated using GSE12021 and GSE1919 datasets. TM9SF2 was upregulated in the synovial tissues of OA at both mRNA and protein levels. The relationship between TM9SF2 and several functional annotations, such as antigen processing and presentation, lysosome, phagosome, Fcγ-mediated phagocytosis, and tyrosine metabolism, was identified. TM9SF2 and macrophages M2 were significantly correlated. After silencing TM9SF2 in THP-1-derived macrophages M2, a significantly reduced phagocytosis and attenuated activation of PLC-γ1 were observed.ConclusionA sulfur metabolism-associated six-gene signature for OA diagnosis was constructed and upregulation of the phagocytosis-associated gene, TM9SF2, was identified. The findings are expected to deepen our understanding of the molecular mechanism underlying OA development and be used as potential therapeutic targets.

A zinc metabolism-related gene signature for predicting prognosis and characteristics of breast cancer.

Breast cancer is one of the most serious and prevalent malignancies. Zinc is commonly known to play a crucial role in the development and progression of breast cancer; however, the detailed mechanisms underlying this role are not well understood. This study aimed to develop a zinc metabolism-related gene (ZMRG) signature based on a multi-database study to predict patient prognosis and investigate the relationship between drug therapy response and immune enrichment. Data for breast cancer samples from The Cancer Genome Atlas and Gene Expression Omnibus databases were screened for zinc metabolism-related genes using the Molecular Signature Database. Cox and Least Absolute Shrinkage and Selection Operator regressions were performed to construct a ZMRG signature. To assess the predictive performance of the gene signature, Kaplan-Meier analysis and receiver operating characteristic curves were used. Additionally, we utilised single-sample gene set enrichment analysis, the Tumour Immune Estimation Resource, the Genomics of Drug Sensitivity in Cancer database, and the Cancer Therapeutics Response Portal to investigate the association between the tumour microenvironment and drug sensitivity. Quantitative PCR was used to assess the expression of each gene in the signature in breast cancer cell lines and patient samples. Five ZMRGs were identified (ATP7B, BGLAP, P2RX4, SLC39A11, and TH) and a risk profile was constructed for each. Two risk groups, high- and low-risk, were identified in this way, and the high-risk score subgroups were found to have worse prognosis. This risk profile was validated using the GSE42568 dataset. Tumour microenvironment and drug sensitivity analyses showed that the expression of these five ZMRGs was significantly associated with immune response. The high-risk group showed substantial immune cell infiltration and enrichment of immune pathways, and patients were more sensitive to drugs commonly used in breast cancer. The ZMRG signature represents a new prognostic predictor for patients with breast cancer, and may also provide new insights into individualised treatment of breast cancer.

A Lactic Acid Metabolism-Related Gene Signature for Predicting Clinical Outcome and Tumor Microenvironmental Status in Patients with Hepatocellular Carcinoma

This study aims to build a prognostic model based on lactic acid metabolism-related genes (LMRGs) to predict survival outcomes and tumor microenvironment status of Hepatocellular carcinoma (HCC) patients. The model was used to calculate riskscores of clinical samples. Survival analysis and Cox regression analysis were conducted to verify the independence and reliability of the riskscore to determine its clinical significance in prognosis evaluation of HCC. Additionally, we conducted a comprehensive analysis of tumor mutation burden (TMB), immune cell infiltration, and gene set molecular function in the high- and low-risk groups. We obtained 134 LMRGs mainly involved in cellular calcium homeostasis and calcium signaling pathways. The LMRGs in the risk assessment model included PFKFB4, SLC16A3, ADRA2B, SLC22A1, QRFPR, and PROK1. This study discovered much shorter overall survival and median survival time of patients with higher riskscores when compared to those with lower riskscores. It was indicated that for independent prediction of patients’ prognosis, the riskscore had a significant clinical value. A remarkable difference was also found regarding TMB between the two groups. Finally, cell experiments demonstrated that the knockout of PFKFB4 and SLC16A3 genes suppressed lactate. Our research demonstrated that the riskscore, established based on LMRGs, is a promising biomarker.