Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma.

BACKGROUND: As one of the common subtypes of non-small lung cancer, lung squamous cell carcinoma (LUSC) patients with advanced stage have few choices of treatment strategies. Therefore, it is urgent to discover genes that are associated with the survival and efficacy of immunotherapies. METHOD: Differential gene expression analyses were conducted using TCGA LUSC bulk-sequencing and single-cell RNA-sequencing data. Prognostic genes were identified from the TCGA LUSC cohort. Protein expression validation and survival analyses were performed. Experiments were conducted to explore the underlying mechanisms. In addition, the correlation between gene expression and pathological response to adjuvant immunochemotherapy was also investigated. RESULTS: After a series of bioinformatic analyses, solute carrier family 2 member 1(SLC2A1), encoding glucose transporter-1 (GLUT1), was found to be differentially expressed between tumor and normal tissues. GLUT1 was subsequently identified as an independent prognostic factor for LUSC. GSEA analysis revealed the glycolysis metabolism pathway of KEGG enriched in SLC2A1high tumor tissues. LASSO analyses revealed that tumor tissues with high expression of SLC2A1 were associated with high levels of protein lactylation. We found that SLC2A1 was preferentially expressed by SPP1+ macrophages in the tumor microenvironment, and the expression of SLC2A1 was associated with the abundance of SPP1+ macrophages. Immunofluorescence demonstrated GLUT1 and HIF1α colocalization in tumor-infiltrating macrophages. In vitro experiments showed HIF-1α-induced macrophage polarization under hypoxia, and GLUT1 inhibition blocked this polarization. In addition, SLC2A1 was negatively associated with the common immune checkpoint molecules, such as programmed cell death 1(PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte associated protein 4 (CTLA4) and lymphocyte activating 3 (LAG3), while showed a positive association with CD44. Finally, we observed that there was a significant correlation between pre-adjuvant-treatment GLUT1 expression and the pathological response. CONCLUSION: SLC2A1 expression was differentially upregulated in tumor tissues, and elevated GLUT1 expression was associated with worse survival and poor pathological response to adjuvant immunochemotherapy. Upregulation of GLUT1 promoted macrophage polarization into the M2 phenotype. The findings will contribute to guiding the treatment selection for LUSC patients and providing personalized immunotherapy strategies.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Carcinogenic Role and Clinical Significance of Histone H3-H4 Chaperone Anti-silencing Function 1 B (ASF1B) in Lung Adenocarcinoma.

Histone H3-H4 chaperone anti-silencing function 1 (ASF1) plays an important role in the polymerization, transport, and modification of histones. However, the significance of ASF1B in lung adenocarcinoma (LUAD) is largely overlooked. We investigated the aberrant expression of ASF1B in LUAD and its potential link to patient survival using multiple databases. ASF1B-overexpressing and knockdown cell lines were constructed to explore its effects on the biological behavior of lung cancer cells. ssGSEA, TMB, TIDE and IMvigor210 cohort were used to explore and validate the association of ASF1B to tumor immunity. Our data suggested that ASF1B was overexpressed in LUAD, and was associated with poor prognosis. ASF1B promoted the proliferation, migration, and invasion of lung cancer cells by regulating the phosphorylation of AKT in vitro. ASF1B was associated with tumor immunity. In summary, ASF1B may promote malignant behavior of LUAD cells, and its overexpression correlates with worse prognosis and better immunotherapy effect.

Comprehensive analysis of m6A modification in lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND: N6-Methyladenosine (m6A) methylation is the most prevalent post-transcriptional modification in mRNA, and plays significant roles in various diseases. Nevertheless, the precise functions of m6A modification in the formation of ALI remain unclear. In this study we explore the transcriptome distribution of m6A methylation and its probable roles of in ALI. METHODS: Lipopolysaccharide (LPS) was utilized to establish an ALI mouse model. Real-time qPCR, Western blotting and m6A dot blot were utilized to assess m6A methylation level and the expression of m6A methylation enzymes. MeRIP-Seq and RNA-seq were utilized to explore differential m6A modifications and differentially expressed genes in ALI mice. The hub genes and enriched pathways were assessed by Real-time qPCR and Western blotting. RESULTS: Our findings showed that overall m6A methylation level was increased in ALI mice lung tissues, accompanied by lower levels of METTL3 and FTO. Notably, the protein expression of these methylases were different in various cells. There were 772 differently expressed m6A peaks in ALI as compared to the control group, with 316 being hypermethylated and 456 being hypomethylated. GO and KEGG analyses demonstrated these differentially methylated genes were associated with the calcium signaling pathway and cAMP signaling pathway. Furthermore, we identified 50 genes with distinct m6A peaks and mRNA expressions by combined analysis of MeRIP-Seq and RNA-Seq. KEGG analysis also demonstrated that these overlapped genes were closely associated with the calcium signaling pathway, cGMP-PKG signaling pathway, etc. Besides, Western blotting results demonstrated that the protein expression of Fibronectin leucine-rich transmembrane protein 3 (Flrt3) as well as the calcium signaling pathway and cGMP-PKG signaling pathway, increased significantly after ALI. CONCLUSIONS: m6A modification was paramount in the pathogenesis of ALI, and provided a foundation for the further investigation in the prevention and treatment of ALI.

Hydroxycitric Acid Alleviated Lung Ischemia-Reperfusion Injury by Inhibiting Oxidative Stress and Ferroptosis through the Hif-1α Pathway.

Lung ischemia-reperfusion injury (LIRI) is a prevalent occurrence in various pulmonary diseases and surgical procedures, including lung resections and transplantation. LIRI can result in systemic hypoxemia and multi-organ failure. Hydroxycitric acid (HCA), the primary acid present in the peel of Garcinia cambogia, exhibits anti-inflammatory, antioxidant, and anticancer properties. However, the effects of HCA on LIRI remain unknown. To investigate the impact of HCA on LIRI in mice, the mice were randomly divided into four groups: the control group, the I/R model group, and the I/R + low- or high-dose HCA groups. Human umbilical vein endothelial cells (HUVECs) were subjected to hypoxia for 12 h followed by reoxygenation for 6 h to simulate in vitro LIRI. The results demonstrated that administration of HCA effectively attenuated lung injury, inflammation, and edema induced by ischemia reperfusion. Moreover, HCA treatment significantly reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels while decreasing iron content and increasing superoxide dismutase (SOD) levels after ischemia-reperfusion insult. Mechanistically, HCA administration significantly inhibited Hif-1α and HO-1 upregulation both in vivo and in vitro. We found that HCA could also alleviate endothelial barrier damage in H/R-induced HUVECs in a concentration-dependent manner. In addition, overexpression of Hif-1α counteracted HCA-mediated inhibition of H/R-induced endothelial cell ferroptosis. In summary, these results indicate that HCA alleviated LIRI by inhibiting oxidative stress and ferroptosis through the Hif-1α pathway.

The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics.

As a multi-substrate transmembrane protease, γ-secretase exists widely in various cells. It controls multiple important cellular activities through substrate cleavage. γ-secretase inhibitors (GSIs) play a role in cancer inhibition by blocking Notch cleavage, and are considered as potential therapeutic strategies for cancer. Currently, GSIs have encouraging performance in preclinical models, yet this success does not translate well in clinical trials. In recent years, a number of breakthrough discoveries have shown us the promise of targeting γ-secretase for the treatment of cancer. Here, we integrate a large amount of data from γ-secretase and its inhibitors and cancer in nearly 30 years, comb and discuss the close connection between γ-secretase and cancer, as well as the potential and problems of current GSIs in cancer treatment. We analyze the possible reasons for the failure performance of current GSIs in clinical trials, and make recommendations for future research areas.

Molecular characteristics and clinical implications of serine/arginine-rich splicing factors in human cancer.

As critical splicing regulators, serine/arginine-rich splicing factors (SRSFs) play pivotal roles in carcinogenesis. As dysregulation of SRSFs may confer potential cancer risks, targeting SRSFs could provide important insights into cancer therapy. However, a global and comprehensive pattern to elaborate the molecular characteristics, mechanisms, and clinical links of SRSFs in a wide variety of human cancer is still lacking. In this study, a systematic analysis was conducted to reveal the molecular characteristics and clinical implications of SRSFs covering more than 10000 tumour samples of 33 human cancer types. We found that SRSFs experienced prevalent genomic alterations and expression perturbations in multiple cancer types. The DNA methylation, m6A modification, and miRNA regulation of SRSFs were all cancer context-dependent. Importantly, we found that SRSFs were strongly associated with cancer immunity, and were capable of predicting response to immunotherapy. And SRSFs had colossal potential for predicting survival in multiple cancer types, including those that have received immunotherapy. Moreover, we also found that SRSFs could indicate the drug sensitivity of targeted therapy and chemotherapy. Our research highlights the significance of SRSFs in cancer occurrence and development, and provides sufficient resources for understanding the biological characteristics of SRSFs, offering a new and unique perspective for developing cancer therapeutic strategies.

Eriocitrin inhibits epithelial-mesenchymal transformation (EMT) in lung adenocarcinoma cells via triggering ferroptosis.

INTRODUCTION: Lung adenocarcinoma (LUAD) is the most prevalent pathological subtype of non-small cell lung cancer (NSCLC), characterized by a high propensity for relapse and metastasis due to epithelial-mesenchymal transition (EMT) of cancer cells. Ferroptosis, a newly discovered regulated cell death modality, is interconnected with the EMT process in certain cancers. Eriocitrin, a natural flavonoid compound, exerts anti-inflammatory and anticancer effects. OBJECTIVES: The aim of this study is to investigate the potential inhibitory effect of eriocitrin on lung adenocarcinoma metastasis and explore whether its underlying mechanism involves ferroptosis induction in cancer cells. METHODS: The CCK8 assay and wound healing assay and transwell were conducted to determine the cell viability and migration ability of A549 and H1299 cells, respectively. EMT process was assessed by western blot and RT-PCR to detect protein and mRNA levels of EMT markers. ROS and cell iron were measured to determine ferroptosis level. RESULTS: Eriocitrin treatment significantly inhibited cell viability and migration ability in a concentration-dependent manner. Furthermore, eriocitrin administration for 24 hours resulted in enhanced expression of E-cadherin, while downregulating vimentin, N-cadherin and snail expression, indicating marked repression of the EMT process. Additionally, eriocitrin significantly induced ferroptosis in A549 and H1299 cells, as evidenced by increased ROS levels, downregulation of Nrf-2, SLC7A11 and GPX4 expression, and enhanced cellular iron accumulation. Moreover, pretreatment with the ferroptosis inhibitor ferrostatin-1 effectively abrogated the inhibitory effects of eriocitrin on EMT. CONCLUSIONS: Our findings further support the anti-cancer properties of eriocitrin, as evidenced by its ability to inhibit the EMT process in LUAD cells, which is partially mediated through induction of ferroptosis in cancer cells.

Systematic analysis of histone acetylation regulators across human cancers.

BACKGROUND: Histone acetylation (HA) is an important and common epigenetic pathway, which could be hijacked by tumor cells during carcinogenesis and cancer progression. However, the important role of HA across human cancers remains elusive. METHODS: In this study, we performed a comprehensive analysis at multiple levels, aiming to systematically describe the molecular characteristics and clinical relevance of HA regulators in more than 10000 tumor samples representing 33 cancer types. RESULTS: We found a highly heterogeneous genetic alteration landscape of HA regulators across different human cancer types. CNV alteration may be one of the major mechanisms leading to the expression perturbations in HA regulators. Furthermore, expression perturbations of HA regulators correlated with the activity of multiple hallmark oncogenic pathways. HA regulators were found to be potentially useful for the prognostic stratification of kidney renal clear cell carcinoma (KIRC). Additionally, we identified HDAC3 as a potential oncogene in lung adenocarcinoma (LUAD). CONCLUSION: Overall, our results highlights the importance of HA regulators in cancer development, which may contribute to the development of clinical strategies for cancer treatment.

Optical time-stretch imaging flow cytometry in the compressed domain.

Imaging flow cytometry based on optical time-stretch (OTS) imaging combined with a microfluidic chip attracts much attention in the large-scale single-cell analysis due to its high throughput, high precision, and label-free operation. Compressive sensing has been integrated into OTS imaging to relieve the pressure on the sampling and transmission of massive data. However, image decompression brings an extra overhead of computing power to the system, but does not generate additional information. In this work, we propose and demonstrate OTS imaging flow cytometry in the compressed domain. Specifically, we constructed a machine-learning network to analyze the cells without decompressing the images. The results show that our system enables high-quality imaging and high-accurate cell classification with an accuracy of over 99% at a compression ratio of 10%. This work provides a viable solution to the big data problem in OTS imaging flow cytometry, boosting its application in practice.

BZW1 as an oncogene is associated with patient prognosis and the immune microenvironment in glioma.

BACKGROUND: Glioma is the most common primary tumor in the human central nervous system. This study was designed to explore the expression of BZW1 in glioma and its relevance to the clinicopathological features and outcome of glioma patients. METHODS: Glioma transcription profiling data were obtained from The Cancer Genome Atlas (TCGA). TIMER2, GEPIA2, GeneMANIA, and Metascape were searched in the present study. Cell and animal experiments were conducted to verify the effect of BZW1 on glioma cell migration in vitro and in vivo. Transwell assays, western blotting and immunofluorescence assays were performed. RESULTS: We found that BZW1 was highly expressed in gliomas and correlated with poor prognosis. BZW1 could promote glioma proliferation. GO/KEGG analysis revealed that BZW1 was involved in collagen-containing extracellular matrix and was correlated with ECM-receptor interactions, transcriptional misregulation in cancer and the IL-17 signaling pathway. In addition, BZW1 was also associated with the glioma tumor immune microenvironment. CONCLUSION: BZW1 can promote glioma proliferation and progression, and its high expression is correlated with a poor prognosis. BZW1 is also associated with the tumor immune microenvironment of glioma. This study may facilitate further understanding of the critical role of BZW1 in human tumors, including gliomas.

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage.

Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis.

Eriocitrin attenuates sepsis-induced acute lung injury in mice by regulating MKP1/MAPK pathway mediated-glycolysis.

Metabolic reprogramming has been shown to aggravate sepsis-induced acute lung injury. In particular, enhanced glycolysis is closely associated with inflammation and oxidative stress. Eriocitrin (ERI) is a natural flavonoid found in citrus fruit that exhibits various pharmacological activities, with antioxidant, anti-inflammatory, anti-diabetic, and anti-tumor properties. However, the role of ERI in lung injury is not well understood. We established a septic mouse model of acute lung injury (ALI) using lipopolysaccharide (LPS) for induction. Primary peritoneal macrophages were isolated to verify the relevant molecular mechanism. Tissues were assessed for lung pathology, pro-inflammatory cytokines, markers of oxidative stress, and protein and mRNA expression levels. In vivo experiments showed that ERI effectively alleviated LPS-induced pathological injury, suppress the inflammatory response (TNF-α, IL-1ß, IL-6 levels) and decreased oxidative stress (MDA, ROS) in murine lung tissue. In vitro, ERI increased the resistance of LPS-treated cells to excessive inflammation and oxidative stress by inhibiting the enhancement of glycolysis (indicated by expression levels of HIF-1α, HK2, LDHA, PFKFB3, and PKM2). Specifically, the beneficial effects of ERI following LPS-induced lung injury occurred through promoting the expression of MKP1, which mediates the inactivation of the MAPK pathway to inhibit enhanced glycolysis. These results demonstrate that ERI has a protective effect on sepsis-induced ALI by regulating MKP1/MAPK pathway mediated-glycolysis. Hence, ERI is a promising candidate against ALI via inhibiting glycolysis.

Identification of four metabolic subtypes and key prognostic markers in lung adenocarcinoma based on glycolytic and glutaminolytic pathways.

BACKGROUND: Glucose and glutamine are the main energy sources for tumor cells. Whether glycolysis and glutaminolysis play a critical role in driving the molecular subtypes of lung adenocarcinoma (LUAD) is unknown. This study attempts to identify LUAD metabolic subtypes with different characteristics and key genes based on gene transcription profiling data related to glycolysis and glutaminolysis, and to construct prognostic models to facilitate patient outcome prediction. METHODS: LUAD related data were obtained from the Cancer Genome Atlas and Gene Expression Omnibus, including TCGA-LUAD, GSE42127, GSE68465, GSE72094, GSE29013, GSE31210, GSE30219, GSE37745, GSE50081. Unsupervised consensus clustering was used for the identification of LUAD subtypes. Differential expression analysis, weighted gene co-expression network analysis (WGCNA) and CytoNCA App in Cytoscape 3.9.0 were used for the screening of key genes. The Cox proportional hazards model was used for the construction of the prognostic risk model. Finally, qPCR analysis, immunohistochemistry and immunofluorescence colocalization were used to validate the core genes of the model. RESULT: This study identified four distinct characterized LUAD metabolic subtypes, glycolytic, glutaminolytic, mixed and quiescent types. The glycolytic type had a worse prognosis than the glutaminolytic type. Nine genes (CXCL8, CNR1, AGER, ALB, S100A7, SLC2A1, TH, SPP1, LEP) were identified as hub genes driving the glycolytic/glutaminolytic LUAD. In addition, the risk assessment model constructed based on three genes (SPP1, SLC2A1 and AGER) had good predictive performance and could be validated in multiple independent external LUAD cohorts. These three genes were differentially expressed in LUAD and lung normal tissues, and might be potential prognostic markers for LUAD. CONCLUSION: LUAD can be classified into four different characteristic metabolic subtypes based on the glycolysis- and glutaminolysis-related genes. Nine genes (CXCL8, CNR1, AGER, ALB, S100A7, SLC2A1, TH, SPP1, LEP) may play an important role in the subtype-intrinsic drive. This metabolic subtype classification, provides new biological insights into the previously established LUAD subtypes.

Single-cell RNA sequencing analysis revealed cellular and molecular immune profiles in lung squamous cell carcinoma.

Although breakthroughs have been made in the treatment of non-small cell lung cancer, there are only a few choices for advanced-stage or recurrent lung squamous cell carcinoma (LUSC) patients. In our study, we identified 7 major cell types in thedepicted the immunolandscape of LUSC microenvironment using single-cell RNA sequencing. We found that an immunosuppressive receptor, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), was highly expressed by regulatory T cells (Tregs) and exhausted CD8+T cells, suggesting that upregulation of TIGIT might promote an immunosuppressive microenvironment and inhibit the cytotoxic ability of CD8+T cells. We also identified tumor-associated neutrophil (TAN), characterized by CXCR2, CSF3R and CXCL8, in the tumor region, and TANs upregulated the expression of interleukin 1 receptor antagonist (IL1RN) which suggested that TAN might exert an immunosuppressive role via expressing IL1RN. Furthermore, the number of SPP1+ macrophages(SPP1+M) significantly increased in tumor microenvirnment, which was correlated with the poor survival of patients. Additionally, regulatory networks based on SPP1+M revealed that the disparities of several ligand-receptor pairs existed between tumor and normal tissues. Among these pairs, SPP1-CD44 showed the most interactions between SPP1+M and other cell types. Our results provided deep insight into the immune landscape of LUSC and an essential resource for drug discovery in the future.

Crosstalk between neutrophil extracellular traps and immune regulation: insights into pathobiology and therapeutic implications of transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated death, occurring during or within 6 hours after transfusion. Reports indicate that TRALI can be categorized as having or lacking acute respiratory distress syndrome (ARDS) risk factors. There are two types of TRALI in terms of its pathogenesis: antibody-mediated and non-antibody-mediated. The key initiation steps involve the priming and activation of neutrophils, with neutrophil extracellular traps (NETs) being established as effector molecules formed by activated neutrophils in response to various stimuli. These NETs contribute to the production and release of reactive oxygen species (ROS) and participate in the destruction of pulmonary vascular endothelial cells. The significant role of NETs in TRALI is well recognized, offering a potential pathway for TRALI treatment. Moreover, platelets, macrophages, endothelial cells, and complements have been identified as promoters of NET formation. Concurrently, studies have demonstrated that the storage of platelets and concentrated red blood cells (RBC) can induce TRALI through bioactive lipids. In this article, recent clinical and pre-clinical studies on the pathophysiology and pathogenesis of TRALI are reviewed to further illuminate the mechanism through which NETs induce TRALI. This review aims to propose new therapeutic strategies for TRALI, with the hope of effectively improving its poor prognosis.

Identification of cuproptosis-related subtypes in lung adenocarcinoma and its potential significance.

Cuproptosis is a novel and unique cell death mode that has attracted significant interest in recent years. Little is currently known about whether cuproptosis-related genes (CRGs) are associated with the pathophysiology and survival of patients with lung adenocarcinoma (LUAD). The present study sought to characterize the transcriptional and genetic alteration of CRGs in LUAD and its potential significance in the tumor microenvironment and predicting the prognosis of LUAD. The secondary eventual aim was to study the role of CRGs in predicting immunotherapy response and its clinical value combined with the TNM stage. We found that several CRGs, including FDX1, DLD, SLC31A1, and MTF1, were enriched in macrophages in our single-cell RNA-seq data. Three distinct molecular subtypes were identified and correlated with clinicopathological characteristics, prognosis, biological pathways, and tumor microenvironment (TME) in LUAD. We developed a cuproptosis-related gene score (CRG_score) and validated it in three independent cohorts and clinical subtypes. The low CRG_score group, characterized by a greater immune score, immunophenoscore (IPS), lower tumor immune dysfunction and exclusion (TIDE) score, and T-cell dysfunction score, had a better prognosis, suggesting that the low CRG_score group responded more favorably to immunotherapy, which was validated in the anti-PD-1/L1 immunotherapy cohort (IMvigor210). In contrast, the high CRG_score group was more sensitive to targeted therapy and chemotherapy, with a higher cancer stem cell (CSC) index and lower half-maximal inhibitory concentration (IC50) for many drugs. Given the established crosstalk between CRG_score and tumor TNM stage, we developed an accurate nomogram for clinical application of the CRG_score. Taken together, our rigorous and comprehensive examination of CRGs in LUAD identified their potential functions in TME, clinicopathological characteristics, drug sensitivity, and prognosis. These findings improve the current understanding of cuproptosis in LUAD, paving the way for more accurate prognosis assessment and tailored treatment for this patient population.

Mitophagy: A novel perspective for insighting into cancer and cancer treatment.

BACKGROUND: Mitophagy refers to the selective self-elimination of mitochondria under damaged or certain developmental conditions. As an important regulatory mechanism to remove damaged mitochondria and maintain the internal and external cellular balance, mitophagy plays pivotal roles in carcinogenesis and progression as well as treatment. MATERIALS AND METHODS: Here, we combined data from recent years to comprehensively describe the regulatory mechanisms of mitophagy and its multifaceted significance in cancer, and discusse the potential of targeted mitophagy as a cancer treatment strategy. RESULTS: The molecular mechanisms regulating mitophagy are complex, diverse, and cross-talk. Inducing or blocking mitophagy has the same or completely different effects in different cancer contexts. Mitophagy plays an indispensable role in regulating cancer metabolic reprogramming, cell stemness, and chemotherapy resistance for better adaptation to tumor microenvironment. In cancer cell biology, mitophagy is considered to be a double-edged sword. And to fully understand the role of mitophagy in cancer development can provide new targets for cancer treatment in clinical practice. CONCLUSIONS: This review synthesizes a large body of data to comprehensively describe the molecular mechanisms of mitophagy and its multidimensional significance in cancer and cancer treatment, which will undoubtedly deepen the understanding of mitophagy.

Comprehensive analysis reveals the potential value of inflammatory response genes in the prognosis, immunity, and drug sensitivity of lung adenocarcinoma.

BACKGROUND: Although the relationship between inflammatory response and tumor has been gradually recognized, the potential implications of of inflammatory response genes in lung adenocarcinoma (LUAD) remains poorly investigated. METHODS: RNA sequencing and clinical data were obtained from multiple independent datasets (GSE29013, GSE30219, GSE31210, GSE37745, GSE42127, GSE50081, GSE68465, GSE72094, TCGA and GTEx). Unsupervised clustering analysis was used to identify different tumor subtypes, and LASSO and Cox regression analysis were applied to construct a novel scoring tool. We employed multiple algorithms (ssGSEA, CIBERSORT, MCP counter, and ESTIMATE) to better characterize the LUAD tumor microenvironment (TME) and immune landscapes. GSVA and Metascape analysis were performed to investigate the biological processes and pathway activity. Furthermore, 'pRRophetic' R package was used to evaluate the half inhibitory concentration (IC50) of each sample to infer drug sensitivity. RESULTS: We identified three distinct tumor subtypes, which were related to different clinical outcomes, biological pathways, and immune characteristics. A scoring tool called inflammatory response gene score (IRGS) was established and well validated in multiple independent cohorts, which could well divide patients into two subgroups with significantly different prognosis. High IRGS patients, characterized by increased genomic variants and mutation burden, presented a worse prognosis, and might show a more favorable response to immunotherapy and chemotherapy. Additionally, based on the cross-talk between TNM stage, IRGS and patients clinical outcomes, we redefined the LUAD stage, which was called 'IRGS-Stage'. The novel staging system could distinguish patients with different prognosis, with better predictive ability than the conventional TNM staging. CONCLUSIONS: Inflammatory response genes present important potential value in the prognosis, immunity and drug sensitivity of LUAD. The proposed IRGS and IRGS-Stage may be promising biomarkers for estimating clinical outcomes in LUAD patients.

Integrated Analysis Reveals the Potential Significance of HDAC Family Genes in Lung Adenocarcinoma.

Histone deacetylases comprise a family of 18 genes, and classical HDACs are a promising class of novel anticancer drug targets. However, to date, no systematic study has been comprehensive to reveal the potential significance of these 18 genes in lung adenocarcinoma (LUAD). Here, we used a systematic bioinformatics approach to comprehensively describe the biological characteristics of the HDACs in LUAD. Unsupervised consensus clustering was performed to identify LUAD molecular subtypes. The ssGSEA, CIBERSORT, MCP counter, and ESTIMATE algorithms were used to depict the tumor microenvironment (TME) landscape. The Cox proportional hazards model and LASSO regression analyses were used to construct the HDAC scoring system for evaluating the prognosis of individual tumors. In this study, three distinct HDAC-mediated molecular subtypes were determined, which were also related to different clinical outcomes and biological pathways. HDACsCluster-C subtype had lowest PD-L1/PD-1/CTLA4 expression and immune score. The constructed HDAC scoring system (HDACsScore) could be used as an independent predictor to assess patient prognosis and effectively identify patients with different prognosis. High- and low-HDACsScore groups presented distinct genetic features, immune infiltration, and biological processes. The high-HDACsScore group was more likely to benefit from immunotherapy, as well as from the application of common chemotherapeutic agents (cyclopamine, docetaxel, doxorubicin, gemcitabine, paclitaxel, and pyrimethamine). Overall, HDAC family genes play important roles in LUAD, and the three LUAD subtypes and the HDAC scoring system identified in this study would help enhance our perception of LUAD prognostic differences and provide important insights into the efficacy of immunotherapy and chemotherapy.