AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors.

Aberrant alternative splicing (AS) events have been identified in a variety of cancers. Although somatic mutations of splicing factors and dysregulation of RNA-binding proteins (RBPs) have been linked to AS and tumor malignancy, it remains unclear how upstream mechanisms contribute to cancer development via alternative gene splicing. In this issue of the JCI, Wenrui Zhang and colleagues identified the role of asparagine endopeptidase (AEP), an intracellular cysteine endopeptidase, in promoting solid tumor-associated RNA splicing. The authors demonstrated that tumor environmental factors such as oxygen and nutrient deprivation induce the activity of AEP in a HIF1A-dependent manner. The activated AEP, in turn, cleaves an RNA helicase DDX3X to promote its nuclear retention. The authors further showed that this DDX3X nuclear fraction engages with splicing machinery to induce AS events in several cancer cells. These findings suggest that targeting an AEP-dependent aberrant RNA splicing cascade may facilitate therapeutics for solid tumors.

Intratumor Mycoplasma promotes the initiation and progression of hepatocellular carcinoma.

The carcinogenesis and progression of hepatocellular carcinoma (HCC) are closely related to viral infection and intestinal bacteria. However, little is known about bacteria within the HCC tumor microenvironment. Here, we showed that intratumoral Mycoplasma hyorhinis (M. hyorhinis) promoted the initiation and progression of HCC by enhancing nuclear ploidy. We quantified M. hyorhinis in clinical tissue specimens of HCC and observed that patients with high M. hyorhinis load had poor prognosis. We found that gastrointestinal M. hyorhinis can retrogradely infect the liver through the oral-duodenal-hepatopancreatic ampulla route. We further found that the increases in mononuclear polyploidy and cancer stemness resulted from mitochondrial fission caused by intracellular M. hyorhinis. Mechanistically, M. hyorhinis infection promoted the decay of mitochondrial fusion protein (MFN) 1 mRNA in an m6A-dependent manner. Our findings indicated that M. hyorhinis infection promoted pathological polyploidization and suggested that Mycoplasma clearance with antibiotics or regulating mitochondrial dynamics might have the potential for HCC therapy.

Label free and high-throughput discrimination of cells at a bipolar electrode array using the AC electrodynamics.

BACKGROUND: Cell characterization and manipulation play an important role in biological and medical applications. Cell viability evaluation is of significant importance for cell toxicology assay, dose test of anticancer drugs, and other biochemical stimulations. The electrical properties of cells change when cells transform from healthy to a pathological state. Current methods for evaluating cell viability usually requires a complicated chip and the throughput is limited. RESULTS: In this paper, a bipolar electrode (BPE) array based microfluidic device for assessing cell viability is exploited using AC electrodynamics. The viability of various cells including yeast cells and K562 cells, can be evaluated by analyzing the electro-rotation (ROT) speed and direction of cells, as well as the dielectrophoresis (DEP) responses of cells. Firstly, the cell viability can be identified by the position of the cell captured on the BPE electrode in terms of DEP force. Besides, cell viability can also be evaluated based on both the cell rotation speed and direction using ROT. Under the action of travelling wave dielectric electrophoresis force, the cell viability can also be distinguished by the rotational motion of cells on bipolar electrode edges. SIGNIFICANCE: This study demonstrates the utility of BPEs to enable scalable and high-throughput AC electrodynamics platforms by imparting a flexibility in chip design that is unparalleled by using traditional electrodes. By using BPEs, our proposed new technique owns wide application for cell characterization and viability assessment in situ detection and analysis.

Ferritin light chain promotes the reprogramming of glioma immune microenvironment and facilitates glioma progression.

Background: Tumor-associated macrophages (TAMs), the most abundant non-tumor cell population in the glioma microenvironment, play a crucial role in immune evasion and immunotherapy resistance of glioblastoma (GBM). However, the regulatory mechanism of the immunosuppressive TME of GBM remains unclear. Methods: Bioinformatics were used to analyse the potential role of ferritin light chain (FTL) in GBM immunology and explore the effects of FTL on the reprogramming of the GBM immune microenvironment and GBM progression. Results: The FTL gene was found to be upregulated in TAMs of GBM at both the bulk and single-cell RNA-seq levels. FTL contributed to the protumor microenvironment by promoting M2 polarization in TAMs via inhibiting the expression of iPLA2ß to facilitate the ferroptosis pathway. Inhibition of FTL in TAMs attenuated glioma angiogenesis, promoted the recruitment of T cells and sensitized glioma to anti-PD1 therapy. Conclusion: Our study suggested that FTL promoted the development of an immunosuppressive TME by inducing M2 polarization in TAMs, and inhibition of FTL in TAMs reprogrammed the TME and sensitized glioma to anti-PD1 therapy, providing a new strategy for improving the therapeutic effect of anti-PD1.

Gut microbial fatty acid isomerization modulates intraepithelial T cells.

The human gut microbiome constantly converts natural products derived from the host and diet into numerous bioactive metabolites1-3. Dietary fats are essential micronutrients that undergo lipolysis to release free fatty acids (FAs) for absorption in the small intestine4. Gut commensal bacteria modify some unsaturated FAs-for example, linoleic acid (LA)-into various intestinal FA isomers that regulate host metabolism and have anticarcinogenic properties5. However, little is known about how this diet-microorganism FA isomerization network affects the mucosal immune system of the host. Here we report that both dietary factors and microbial factors influence the level of gut LA isomers (conjugated LAs (CLAs)) and that CLAs in turn modulate a distinct population of CD4+ intraepithelial lymphocytes (IELs) that express CD8αα in the small intestine. Genetic abolition of FA isomerization pathways in individual gut symbionts significantly decreases the number of CD4+CD8αα+ IELs in gnotobiotic mice. Restoration of CLAs increases CD4+CD8αα+ IEL levels in the presence of the transcription factor hepatocyte nuclear factor 4γ (HNF4γ). Mechanistically, HNF4γ facilitates CD4+CD8αα+ IEL development by modulating interleukin-18 signalling. In mice, specific deletion of HNF4γ in T cells leads to early mortality from infection by intestinal pathogens. Our data reveal a new role for bacterial FA metabolic pathways in the control of host intraepithelial immunological homeostasis by modulating the relative number of CD4+ T cells that were CD4+CD8αα+.

Impact of HER2 on prognosis and benefit from adjuvant chemotherapy in stage II/III gastric cancer patients: a multicenter observational study.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a well-developed therapeutic target in breast and gastric cancer (GC). However, the impact of HER2 on survival and benefit from fluorouracil-based adjuvant chemotherapy remains unclear in patients with GC. MATERIALS AND METHODS: This multicenter cohort study involved 5622 consecutive stage II/III GC patients. HER2 expression was assessed prospectively via immunohistochemistry (IHC). The staining intensity was graded on a scale of 0 to 3+. An IHC score of 2+or 3+was defined as high expression, and a score of 3+was defined as overexpression. RESULTS: HER2 overexpression was independently associated with a lower 5-year overall survival (OS) in stage II [hazard ratio (HR), 2.10; 95% CI: 1.41-3.11], but not in stage III GC (HR, 1.00; 95% CI, 0.82-1.20). Further analysis revealed that stage II patients with high HER2 expression showed a poorer response to chemotherapy than stage II patients with low HER2 expression ( Pinteraction =0.024). The HRs for 5-year OS were 0.51 (95% CI, 0.38-0.70) for stage II patients with low HER2 expression, 0.58 (95% CI, 0.51-0.66) for stage III patients with low HER2 expression, 1.13 (95% CI, 0.61-2.09) for stage II patients with high HER2 expression, and 0.47 (95% CI, 0.36-0.61) for stage III patients with high HER2 expression. CONCLUSIONS: Fluorouracil-based adjuvant chemotherapy is insufficient for stage II GC patients with high HER2 expression, indicating that prospective trials are required to validate alternative HER2-targeted adjuvant therapies in the individuals above.

High Body Mass Index Was Associated With Human Epidermal Growth Factor Receptor 2-Positivity, Histological Grade and Disease Progression Differently by Age.

Background: Breast cancer is the most commonly occurring cancer among women. The relationship between the obesity paradox and breast cancer is still unclear. The goal of this study is to elucidate the association between high body mass index (BMI) and pathological findings by age. Methods: We collected BMI information pertinent to breast cancer patients from the Gene Expression Omnibus (GEO) database. We use a BMI of 25 as a boundary, and those greater than 25 are defined as high BMI. Besides, we segregated the patients based on age into two age groups: < 55 years, and > 55 years. In this study, R × C Chi-square for trend and binary logistic regression was used to estimate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Results: Higher BMI was associated with less breast cancer incidence in females younger than 55 years of age (OR = 0.313, CI: 0.240 - 0.407). High BMI was associated with human epidermal growth factor receptor 2 (HER2) positivity in breast cancer patients of less than 55 years (P < 0.001), but not in the older patients. High BMI was associated with histological grade lower than 2 in the breast cancer patients older than 55 years, but not in younger patients (OR = 0.288, CI: 0.152 - 0.544). Besides, high BMI was associated with worse progression-free survival in younger breast cancer patients, but not in older patients (P < 0.05). Conclusions: Our results described a significant relationship between breast cancer incidence and BMI at different ages and benefit breast cancer patients to implement strategies to control their BMI for reducing the recurrence and distant recurrence.

LncGMDS-AS1 promotes the tumorigenesis of colorectal cancer through HuR-STAT3/Wnt axis.

Chronic inflammation promotes the tumorigenesis and cell stemness maintenance of colorectal cancer (CRC). However, the bridge role of long noncoding RNA (lncRNA) in linking chronic inflammation to CRC development and progression needs better understanding. Here, we elucidated a novel function of lncRNA GMDS-AS1 in persistently activated signal transducer and transcription activator 3 (STAT3) and Wnt signaling and CRC tumorigenesis. Interleukin-6 (IL-6) and Wnt3a induced lncRNA GMDS-AS1 expression, which was highly expressed in the CRC tissues and plasma of CRC patients. GMDS-AS1 knockdown impaired the survival, proliferation and stem cell-like phenotype acquisition of CRC cells in vitro and in vivo. We performed RNA sequencing (RNA-seq) and mass spectrometry (MS) to probe target proteins and identify their contributions to the downstream signaling pathways of GMDS-AS1. In CRC cells, GMDS-AS1 physically interacted with the RNA-stabilizing protein HuR, thereby protecting the HuR protein from polyubiquitination- and proteasome-dependent degradation. HuR stabilized STAT3 mRNA and upregulated the levels of basal and phosphorylated STAT3 protein, persistently activating STAT3 signaling. Our research revealed that the lncRNA GMDS-AS1 and its direct target HuR constitutively activate STAT3/Wnt signaling and promote CRC tumorigenesis, the GMDS-AS1-HuR-STAT3/Wnt axis is a therapeutic, diagnostic and prognostic target in CRC.

IDH2, a novel target of OGT, facilitates glucose uptake and cellular bioenergy production via NF-κB signaling to promote colorectal cancer progression.

BACKGROUND: Although isocitrate dehydrogenase 2 (IDH2) mutations have been the hotspots in recent anticancer studies, the impact of wild-type IDH2 on cancer cell growth and metabolic alterations is still elusive. METHODS: IDH2 expression in CRC tissues was evaluated by immunohistochemistry, and the correlation between the expression level and the patient's survival rate was analyzed. Cell functional assays included CCK8 and colony formation for cell proliferation in vitro and ectopic xenograft as in vivo experimental model for tumor progression. A targeted metabolomic procedure was performed by liquid chromatography/tandem mass spectrometry to profile the metabolites from glycolysis and tricarboxylic acid (TCA) cycle. Mitochondrial function was assessed by measuring cellular oxygen consumption (OCR) and mitochondrial membrane potential (ΔΨ). Confocal microscope analysis and Western blotting were applied to detect the expression of GLUT1 and NF-κB signaling. O-GlcNAcylation and the interaction of IDH2 with OGT were confirmed by co-immunoprecipitation, followed by Western blotting analysis. RESULTS: IDH2 protein was highly expressed in CRC tissues, and correlated with poor survival of CRC patients. Wild-type IDH2 promoted CRC cell growth in vitro and tumor progression in xenograft mice. Overexpression of wild-type IDH2 significantly increased glycolysis and TCA cycle metabolites, the ratios of NADH/NAD+ and ATP/ADP, OCR and mitochondrial membrane potential (ΔΨ) in CRC cells. Furthermore, α-KG activated NF-κB signaling to promote glucose uptake by upregulating GLUT1. Interesting, O-GlcNAcylation enhanced the protein half-time of IDH2 by inhibiting ubiquitin-mediated proteasome degradation. The O-GlcNAc transferase (OGT)-IDH2 axis promoted CRC progression. CONCLUSION: Wild-type IDH2 reprogrammed glucose metabolism and bioenergetic production via the NF-κB signaling pathway to promote CRC development and progression. O-GlcNAcylation of IDH2 elevated the stability of IDH2 protein. And the axis of OGT-IDH2 played an essential promotive role in tumor progression, suggesting a novel potential therapeutic strategy in CRC treatment.

DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation.

OBJECTIVE: DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer. METHODS: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts. RESULTS: The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein-Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer. CONCLUSIONS: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pan-cancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Visualization and quantification of de novo lipogenesis using a FASN-2A-GLuc mouse model.

Background: De novo lipogenesis (DNL) is a dynamic process that converts excess carbohydrates into fatty acids to maintain cellular homeostasis. Dysregulation of DNL is associated with diverse obesity-related diseases and many tumor types. Therefore, monitoring DNL in real-time with high sensitivity should be highly beneficial when screening therapeutic agents for their potential use as obesity treatments. Methods: A sequence coding for Gaussia luciferase (GLuc) preceded by a 2A peptide was inserted into the murine fatty acid synthase (FASN) genetic locus by homologous recombination to generate FASN-2A-GLuc mice. The luciferase mouse model was evaluated in conditions of physical and pharmacological stimuli by in vivo and ex vivo imaging. Results: The distribution of bioluminescence signals in different organs was identical to the FASN expression: high in white fat, brown fat, and the lungs. In addition, the bioluminescence signals accurately recapitulated the dynamic change of FASN in response to fasting and refeeding conditions. Moreover, with this murine reporter model, we also discovered that fatostatin, a synthetic inhibitor of sterol regulatory element-binding proteins, effectively inhibited DNL in multiple organs, especially in adipose tissues under a high-carbohydrate diet. Conclusions: Our FASN-2A-GLuc reporter mouse model proved to be a sensitive visualization tool for monitoring both systemic and organ-specific DNL in real time.

Exosome-like nanovesicles derived from Phellinus linteus inhibit Mical2 expression through cross-kingdom regulation and inhibit ultraviolet-induced skin aging.

BACKGROUND: Phellinus linteus (PL), which is a typical medicinal fungus, has been shown to have antitumor and anti-inflammatory activities. However, studies on the effect of anti-photoaging are limited. Studies have shown that exosome-like nanovesicles are functional components of many medicinal plants, and miRNAs in exosome-like nanovesicles play a cross-kingdom regulatory role. At present, research on fungi exosome-like nanovesicles (FELNVs) is few. RESULTS: We systematically evaluated the anti-aging effects of PL. FELNVs of PL were isolated, and the functional molecular mechanisms were evaluated. The results of volunteer testing showed that PL had anti-aging activity. The results of component analysis showed that FELNVs were the important components of PL function. FELNVs are nanoparticles (100-260 nm) with a double shell structure. Molecular mechanism research results showed that miR-CM1 in FELNVs could inhibit Mical2 expression in HaCaT cells through cross-kingdom regulation, thereby promoting COL1A2 expression; inhibiting MMP1 expression in skin cells; decreasing the levels of ROS, MDA, and SA-ß-Gal; and increasing SOD activity induced by ultraviolet (UV) rays. The above results indicated that miR-CM1 derived from PL inhibited the expression of Mical2 through cross-kingdom regulation and inhibited UV-induced skin aging. CONCLUSION: miR-CM1 plays an anti-aging role by inhibiting the expression of Mical2 in human skin cells through cross-species regulation.

[Clinical and genetic analysis of a child with disorder of sex development].

OBJECTIVE: To report on the diagnosis and treatment process and clinical characteristics of a child with disorder of sex development (DSD) and to conduct pathological, imaging and genetic analysis for the patient. METHODS: Clinical data of the patient were collected. Genetic testing including chromosomal karyotyping, fluorescence in situ hybridization (FISH), copy number variations (CNVs) analysis, SRY gene detection and multiple ligation-dependent probe amplification (MLPA) were carried out. RESULTS: The patient had a social gender of male, with a history of hypospadia and breast development. Sex hormone tests showed slightly raised prolactin. Imaging results showed bilateral breast hyperplasia, abnormal seminal vesicle glands, rudimentary uterus, and underdeveloped right testis. Intraoperative examination revealed that the child had an ovary on the left and a testis on the right. The pathological results showed fibroadenomatoid changes in the breast. The patient had a karyotype of 46,XX. FISH results showed 46,XX.ish(DXZ1x2, SRYx0). Molecular testing showed that NR0B1, PHEX, CXORF21, GJB1, PQBP1, and COL4A5 genes are duplicated. There was a presence of SRY gene and absence of UYT gene. CONCLUSION: DSD should be considered in patients with genital abnormality and male breast development. Ultrasound, sex hormone test and genetic testing should be performed to confirm the diagnosis of DSD, and molecular testing should be performed if necessary. Individualized treatment of DSD patient requires cooperation of multiple clinical disciplines.

Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type.

Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare skeletal dysplasia characterized by severe disproportionate short stature, short hands and feet, normal intelligence, and facial dysmorphism. Homozygous or compound heterozygous mutations in the natriuretic peptide receptor 2 (NPR2) gene produce growth-restricted phenotypes. The current study was designed to identify and characterize NPR2 loss-of-function mutations in patients with AMDM and to explore therapeutic responses to recombinant growth hormone (rhGH). NPR2 was sequenced in two Chinese patients with AMDM via next generation sequencing, and in silico structural analysis or transcript analysis of two novel variants was performed to examine putative protein changes. rhGH treatment was started for patient 1. Three NPR2 mutations were identified in two unrelated cases: two compound heterozygous mutations c.1112G>A p.(Arg371Gln) and c.2887+2T>C in patient 1 and a homozygous mutation c.329G>A p.(Arg110His) in patient 2, yielding distinct phenotypes. RNA extracted from peripheral blood cells of patient 1 showed alternatively spliced transcripts not present in control cells. Homology modeling analyses suggested that the c.1112G>A p.(Arg371Gln) mutation disrupted the binding of NPR-B homodimer to its ligand (C-type natriuretic peptide) in the extracellular domain as a result of global allosteric effects on homodimer formation. Thus, c.2887+2T>C and c.1112G>A p.(Arg371Gln) in NPR2 were loss-of-function mutations. Furthermore, rhGH therapy in patient 1 increased the patient's height by 0.6SDS over 15 months without adversely affecting the trunk-leg proportion. The short-term growth-promoting effect was equivalent to that reported for idiopathic short stature. Overall, our findings broadened the genotypic spectrum of NPR2 mutations in individuals with AMDM and provided insights into the efficacy of rhGH in these patients.

Bcl-3 promotes TNF-induced hepatocyte apoptosis by regulating the deubiquitination of RIP1.

Tumor necrosis factor-α (TNF) is described as a main regulator of cell survival and apoptosis in multiple types of cells, including hepatocytes. Dysregulation in TNF-induced apoptosis is associated with many autoimmune diseases and various liver diseases. Here, we demonstrated a crucial role of Bcl-3, an IκB family member, in regulating TNF-induced hepatic cell death. Specifically, we found that the presence of Bcl-3 promoted TNF-induced cell death in the liver, while Bcl-3 deficiency protected mice against TNF/D-GalN induced hepatoxicity and lethality. Consistently, Bcl-3-depleted hepatic cells exhibited decreased sensitivity to TNF-induced apoptosis when stimulated with TNF/CHX. Mechanistically, the in vitro results showed that Bcl-3 interacted with the deubiquitinase CYLD to synergistically switch the ubiquitination status of RIP1 and facilitate the formation of death-inducing Complex II. This complex further resulted in activation of the caspase cascade to induce apoptosis. By revealing this novel role of Bcl-3 in regulating TNF-induced hepatic cell death, this study provides a potential therapeutic target for liver diseases caused by TNF-related apoptosis.

Renal outcomes and prognostic factors in patients with type-2 diabetes and chronic kidney disease confirmed by renal biopsy.

AIM: To evaluate the renal outcomes and prognostic factors among patients with type-2 diabetes (T2D) and biopsy-confirmed diabetic nephropathy (DN), non-diabetic renal disease (NDRD) and DN mixed with NDRD (MIX). DESIGN AND METHODS: Patients with both T2D and chronic kidney disease (CKD) who underwent renal biopsy between January 2014 and December 2016 were recruited in this prospective observational study. Participants were divided into DN group, NDRD group, or MIX group according to the baseline pathological diagnosis. The primary endpoint was a composite renal event of end-stage renal disease (ESRD) or ⩾ 40% reduction in estimated glomerular filtration rate (eGFR). RESULTS: Among the 292 participants included, 153 (52.4%) belonged to the DN group, 30 (10.3%) belonged to the NDRD group, and 109 (37.3%) belonged to the MIX group. During the median follow-up of 27 months, the adverse renal events occurred in 132 (44.2%) patients. Compared with NDRD group, the multiple adjusted hazard ratios (HRs) for renal events in patients with DN and MIX groups were 3.900 (95% confidence interval [CI]: 1.103-13.788) and 2.691 (95% CI: 0.662-10.936), respectively. Baseline lower eGFR (HR: 1.159, 95% CI: 1.060-1.266), severe proteinuria (HR: 2.047, 95% CI: 1.227-3.416), lower hemoglobin (HR: 1.170, 95% CI: 1.008-1.267), and a family history of diabetes (HR: 1.138, 95% CI: 1.008-2.285) were independent predictors for adverse renal outcomes in patients with DN. CONCLUSION: In patients with T2D and CKD, pure DN and MIX group displayed a worse renal prognosis than NDRD group. Worse renal function, severe proteinuria, lower hemoglobin, and a family history of diabetes may be associated with adverse renal outcomes in patients with DN.

A Robust Panel Based on Mitochondrial Localized Proteins for Prognostic Prediction of Lung Adenocarcinoma.

Due to high energy and material metabolism requirements, mitochondria are frequently active in tumor cells. Our study found that the high energy metabolism status is positively correlated with the poor prognosis of patients with lung adenocarcinoma. We constructed a scoring system (mitoRiskscore) based on the gene expression of specific mitochondrial localized proteins through univariate and LASSO cox regression. It has been shown that high mitoRiskscore was correlated with a shorter survival time after surgery in patients with lung adenocarcinoma. Compared with the typical TNM grading system, the mitoRiskscore gene panel had higher prediction accuracy. A vast number of external verification results ensured its universality. Additionally, the mitoRiskscore could evaluate the metabolic pattern and chemotherapy sensitivity of the tumor samples. Lung adenocarcinoma with higher mitoRiskscore was more active in glycolysis, and oxidative phosphorylation expression of proliferation-related pathway genes was also significantly upregulated. In contrast, patients with low mitoRiskscore had similar metabolic patterns to normal tissues. In order to improve the accuracy of prediction ability and promote clinical usage, we developed a nomogram that combined mitoRiskscore and clinical prognostic factors to predict the 3-year, 5-year, and 10-year survival rates of patients. We also performed in vitro experiments to verify the function of the key genes in the mitoRiskscore panel. In conclusion, the mitoRiskscore scoring system may assist clinicians to judge the postoperative survival rate and chemotherapy of patients with lung adenocarcinoma.