bims-meluca 2025-08-31 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–08–31
fourteen papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Exploring the metabolic-immune score in advanced NSCLC treated with immunotherapy.
Targeting cancer metabolism: Therapeutic potential of the fatty acid synthase (FASN) inhibitors.
Aberrant DNA methylation and overexpression of NR0B1 are prognostic biomarkers in KEAP1-mutant lung adenocarcinomas.
Glucagon-like peptide-1 receptor agonism improves lung cancer outcomes and tumor growth control.
C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer.
Impact of Baseline Nutritional Status, Psychological Health, Fatigue, and Insomnia on Outcomes of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Retrospective Cohort Study.
Reduced Muscle Loss in Patients With NSCLC Taking Fibrates: Findings From a Retrospective Observational Study.
The relationship between hemoglobin, albumin, lymphocyte, and platelet score and mortality in non-small cell lung cancer.
Hypoxia Exacerbates Inflammatory Signaling in Human Coronavirus OC43-Infected Lung Epithelial Cells.
Risk prediction model for overall survival in lung cancer based on inflammatory and nutritional markers.
Targeting ATP7A-Dependent Copper Metabolic Homeostasis Induces Cuproptosis and Suppresses the Progression of Mutant KRAS-Driven Lung Cancer.
Multi-Omics and Single-Cell Insights Reveal a Lysophosphatidic Acid (LPA)-Mediated Resistant Mechanism to Third Generation EGFR-TKI in Non-Small Cell Lung Cancer.
Disulfidptosis-associated gene signature predicts prognosis and radioresistance in NSCLC.
Pseudohypoxia induced by iron chelator activates tumor immune response in lung cancer.

Sci Rep. 2025 Aug 21. 15(1): 30781

Exploring the metabolic-immune score in advanced NSCLC treated with immunotherapy.

Beliz Bahar Karaoğlan, Ecenur Dursun, İrem Mesci, Mine Soylu Araz, Elif Berna Köksoy.

  Identifying reliable prognostic markers in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) is critical for clinical decision-making. This study introduces the Metabolic and Immune Score (MIS), a novel scoring system combining metabolic and inflammatory markers. A retrospective analysis was conducted on 56 patients with advanced NSCLC treated with ICIs between January 2018 and January 2024. Baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated using 18F-FDG PET-CT imaging. Systemic inflammatory status was assessed using the Lung Immune Prognostic Index (LIPI). Median values for MTV and TLG were used as cut-off points. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients with a LIPI score of 0 demonstrated significantly longer PFS (25.1 vs. 4.1 months, P < 0.001). High TLG levels (> 250.20) were also associated with shorter PFS (4.0 vs. 12.5 months, P = 0.021). On baseline PET-CT, median MTV and TLG were determined as 57.29 cm³ and 250.20, respectively. The MIS, derived from the combination of these two parameters, stratified patients into good, intermediate, and poor prognostic groups. Significant differences in PFS were observed among MIS groups (25.1, 6.3, and 1.5 months; P < 0.001), whereas median OS was not yet reached in the favorable group, and was 13.1 and 5.0 months in the intermediate and poor groups, respectively (P = 0.029). The MIS combines LIPI and TLG, providing a useful tool for predicting outcomes in advanced NSCLC patients treated with immunotherapy. Further validation in larger cohorts is warranted.

Keywords:  Immunotherapy; Lung immune prognostic index; Metabolic tumor volume; Non-small cell lung cancer; Total lesion glycolysis

DOI:  https://doi.org/10.1038/s41598-025-16788-7
Crit Rev Oncol Hematol. 2025 Aug 20. pii: S1040-8428(25)00298-7. [Epub ahead of print]214 104910

Targeting cancer metabolism: Therapeutic potential of the fatty acid synthase (FASN) inhibitors.

Pier Vitale Nuzzo, Silvia Rodrigues, Caroline Fidalgo Ribeiro, Isadora Ferrari Teixeira, Giuseppe Nicolo' Fanelli, Sara Bleve, Francesco Ravera, Hubert Pakula, Filippo Pederzoli, David M Nanus, Massimo Loda.

  Metabolic rewiring is a hallmark of cancer, enabling tumor cells to proliferate rapidly and survive under adverse conditions. Fatty acid synthase (FASN), a key enzyme in de novo lipogenesis, is significantly upregulated in various cancers and is associated with poor prognosis and increased tumor aggressiveness. This review examines the crucial role of FASN in cancer metabolism and evaluates the therapeutic potential of FASN inhibitors. We explore the metabolic pathways critically regulated by FASN and outline its structure, function, and regulatory mechanisms. Overexpression of FASN occurs in cancers such as lung, colon, brain, breast, and prostate, where clinical trials have either been conducted or are ongoing. Pharmacologic inhibition of FASN disrupts lipid biosynthesis, leading to accumulation of metabolic intermediates, induction of metabolic stress, and cell cycle arrest/apoptosis in cancer cells. Denifanstat (TVB-2640), the first-in-class selective FASN inhibitor with favorable pharmacokinetic properties, has demonstrated robust antitumor activity in preclinical models and encouraging results in early-phase clinical studies. Clinical evidence suggests that FASN blockade not only impairs tumor growth but also potentiates the efficacy of existing treatments, including chemotherapy and targeted agents, thereby supporting its integration into combination regimens. Future clinical optimization will require the identification of predictive biomarkers to guide patient selection and treatment stratification.

Keywords:  Cancer Metabolism; De Novo Lipogenesis (DNL); Denifanstat (TVB-2640); Fatty Acid Synthase (FASN) inhibitors; Lipid Biosynthesis; Metabolic Reprogramming

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104910
Discov Oncol. 2025 Aug 27. 16(1): 1641

Aberrant DNA methylation and overexpression of NR0B1 are prognostic biomarkers in KEAP1-mutant lung adenocarcinomas.

Mohamed Elshaer, Ahmed Hammad, Yang Gao, Xiu Jun Wang, Xiuwen Tang.

  The KEAP1-NRF2 pathway regulates cytoprotective responses to endogenous and exogenous stresses induced by reactive oxygen species (ROS) and electrophiles. To maintain oxidative homeostasis, cancer cells increase the transcription of antioxidant genes by acquiring either stabilizing mutations in NRF2 or inactivating mutations in its negative regulator, KEAP1. NR0B1 is a recently identified NRF2 target that supports anchorage-independent growth in KEAP1-mutant non-small cell lung cancer (NSCLC) cells. In this study, we used multi-omics and wet-lab approaches to explore the correlation between KEAP1 mutations, the methylation status of the NR0B1 promoter, NR0B1 gene expression and survival of patients with lung adenocarcinoma (LUAD). We found that the NR0B1 promoter was highly hypomethylated and NR0B1 was significantly overexpressed in KEAP1-mutant LUAD cell lines and patient samples compared to their wild-type counterparts. Correlation analysis showed a strong negative correlation between the hypomethylated CpG sites (NR0B1 promoter) in KEAP1 mutant LUAD patients and NR0B1 gene expression. Moreover, hypomethylation of cg22696549 CpG site (NR0B1 promoter) was associated with poor survival in LUAD patients. Furthermore, the overexpression of NR0B1 was correlated with worse prognosis of LUAD patients. These findings suggest a potential synergy between KEAP1 mutation-associated DNA methylation changes and the transcription factor NRF2, which may drive NR0B1 overexpression. Additionally, this study may enhance the understanding of the molecular mechanisms associated with NR0B1 in lung cancer progression and drug resistance.

Keywords:  DNA methylation; KEAP1; Lung cancer; NR0B1; NRF2

DOI:  https://doi.org/10.1007/s12672-025-03484-1
JCI Insight. 2025 Aug 26. pii: e195484. [Epub ahead of print]

Glucagon-like peptide-1 receptor agonism improves lung cancer outcomes and tumor growth control.

Akhil Goud Pachimatla, Bailey Fitzgerald, Joyce Ogidigo, Meera Bhatia, Randall J Smith, Kalyan Ratnakaram, Sukumar Kalvapudi, Yeshwanth Vedire, Deschana Washington, Robert Vethanayagam Rr, Hua-Hsin Hsiao, Spencer Rosario, Viraj R Sanghvi, Joseph Barbi, Sai Yendamuri.

   BACKGROUND: Emerging evidence indicates a reduced incidence of multiple cancers in users of Glucagon-like peptide-1 receptor agonists (GLP-1RAs), drugs widely used for glycemic control and weight reduction that modulate several key regulators of metabolism. We sought to examine their association with non-small cell lung cancer (NSCLC) outcomes in overweight and obese patients and gain mechanistic insights from mouse models.
METHODS: Two clinical cohorts of overweight and obese NSCLC patients-one undergoing surgical resection (n=1,177, 71 GLP-1RA users) and another receiving immune checkpoint inhibitors (ICIs; n=300, 10 GLP-1RA users), were propensity score matched for relevant covariates and analyzed for clinical outcomes.
RESULTS: GLP-1RA use was associated with increased recurrence-free survival in overweight and obese patients (HR=0.41 [95%CI=0.16-1.04], p=0.026) after lobectomy. GLP-1RA treatment reduced tumor burden in obese but not normal-weight mice and altered the frequency and phenotypes of leukocyte populations and gene expression patterns in obese tumors, crucial to cancer progression and anti-tumor immunity. Concurrent GLP-1RA and immunotherapy was associated with improved overall (0.41 [0.16-1.01], 0.027) and progression-free survival (HR=0.31, [0.10-0.94], 0.019) for patients with advanced NSCLC.
CONCLUSIONS: In our cohort, GLP-1RAs enhanced lung cancer-specific clinical outcomes and augment immunotherapy efficacy. Preclinical evidence suggested this effect to be obesity-restricted and mediated by immune modulation of the tumor microenvironment.
FUNDING: This work was supported by a generous donation from Mr. George Duke to SY; W81XWH-21-1-0377, (GM147497), and RSG-22-071-01-TBE to VRS; 1R01 CA255515-01A1 to SY and JB; and NIH/NCI Cancer Center Support Grants P30CA013696 and P30CA016056.

Keywords:  Clinical Research; Drug therapy; Lung cancer; Obesity; Oncology

DOI:  https://doi.org/10.1172/jci.insight.195484
Cell Rep. 2025 Aug 19. pii: S2211-1247(25)00934-9. [Epub ahead of print]44(9): 116163

C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer.

Ran Liu, Meng Zhao, Xinrui Zhang, Hao Wu, Li Ren, Junqiang Lv, Zhe Liu, Quan Wang, Zhi Yao.

  Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is a hallmark of cancer, yet the mechanisms driving aerobic glycolysis are unclear. In this study, we identified chromosome 19 open reading frame 12 (C19orf12), a gene associated with neurodegeneration, as upregulated in non-small cell lung cancer (NSCLC). Elevated C19orf12 expression is associated with poor prognosis and enhanced metastatic potential in NSCLC cells. High C19orf12 levels repress mitochondrial respiration and decrease glucose flux through the tricarboxylic acid cycle. Mechanistically, C19orf12 interacts with and suppresses the biological function of leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) and downregulates the expression of mitochondrial electron transport chain (ETC) genes. Moreover, C19orf12 increases NSCLC cell sensitivity to the tumoricidal effects of metformin by synergistically inhibiting mitochondrial respiration. These findings highlight C19orf12 as a regulator of mitochondrial metabolism in NSCLC and suggest that its elevated expression could serve as a biomarker to predict improved responses to metformin therapy.

Keywords:  C19orf12; CP: Cancer; CP: Metabolism; LRPPRC; NSCLC; glycolysis; metastasis; metformin; mitochondrial function

DOI:  https://doi.org/10.1016/j.celrep.2025.116163
Kaohsiung J Med Sci. 2025 Aug 24. e70097

Impact of Baseline Nutritional Status, Psychological Health, Fatigue, and Insomnia on Outcomes of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Retrospective Cohort Study.

Yu-Xuan Zhu, Yuan-Yuan Zhang, Xiu-Juan Jiang.

  This study investigated the impact of pretreatment nutritional status, psychological health, fatigue, and insomnia on outcomes of immune checkpoint inhibitors (ICIs) monotherapy in patients with advanced non-small cell lung cancer (NSCLC). A total of 80 patients with stage IV NSCLC were enrolled. Baseline assessments included the Controlling Nutritional Status (CONUT) score, Herth Hope Index (HHI), Hospital Anxiety and Depression Scale (HADS), Brief Fatigue Inventory (BFI), and Athens Insomnia Scale (AIS). Response to ICImonotherapy, along with progression-free survival (PFS) and overall survival (OS), was evaluated at week eight and through subsequent survival analyses. At week eight, partial response (PR), stable disease (SD), and progressive disease (PD) were observed in 31.8%, 33.0%, and 35.2% of patients, respectively. PD patients had significantly higher pretreatment CONUT scores, greater anxiety and depression, and more severe fatigue and insomnia than PR patients. Low nutritional risk was associated with improved OS and PFS. Higher HHI scores and lower HADS-A/D, BFI, and AIS scores correlated with better survival outcomes. In multivariate analysis, anxiety was independently associated with PFS, and depression and fatigue independently predicted OS. Pretreatment nutritional status, psychological health, fatigue, and insomnia significantly influence immunotherapy response and survival in advanced NSCLC. These findings underscore the clinical importance of comprehensive baseline assessments to identify high-risk patients who may benefit from targeted interventions before initiating immunotherapy. Addressing nutritional deficits, psychological distress, fatigue, and insomnia early could potentially enhance treatment response and improve survival outcomes, offering valuable insights for personalized cancer care strategies.

Keywords:  immunotherapy; non‐small cell lung cancer (NSCLC); nutritional status; prognostic factors; psychological health

DOI:  https://doi.org/10.1002/kjm2.70097
J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70016

Reduced Muscle Loss in Patients With NSCLC Taking Fibrates: Findings From a Retrospective Observational Study.

Rahmi Elahjji, Tahj Blow, Rahul Grover, Maurice A Hurd, Richard F Dunne, Bette J Caan, Elizabeth M Cespedes Feliciano, Andrew J Plodkowski, James H Flory, Marcus D Goncalves.

   BACKGROUND: The cancer-anorexia-cachexia syndrome (CACS) is a common and debilitating wasting disorder characterized by loss of skeletal muscle and worse morbidity and mortality. In pre-clinical studies, CACS is associated with loss of peroxisome proliferator-activated receptor alpha (PPAR-α) dependent ketone production in the liver. Fibrates are PPAR-α agonists that are commonly used to treat dyslipidemia. Treating mice with fibrates was found to prevent skeletal muscle loss. We examine whether patients with cancer treated with PPAR-α agonists experience less CACS.
METHODS: We performed a retrospective cohort study of patients (N = 6922) at Memorial Sloan Kettering Cancer Center who were diagnosed with non-small cell lung cancer (NSCLC) between 2002 and 2017 and were incidentally prescribed fenofibrate or gemfibrozil at the time of diagnosis. These patients were compared to a propensity score-matched control set who were not taking either drug. The primary outcome included a composite outcome of CACS, which included significant weight loss before or after the time of diagnosis. Secondary outcomes included change in cross-sectional skeletal muscle area over time as measured in serial CT imaging studies and overall survival. Descriptive statistics, Kaplan-Meier analysis and multivariable logistic regression were performed to compare outcomes between the two groups.
RESULTS: Among patients with NSCLC, 149 were taking fenofibrate or gemfibrozil at the time of diagnosis. A 2:1 propensity score-matched cohort of 298 patients was created that was well-matched with regard to baseline characteristics. Regarding the primary composite outcome, there was no significant difference in the prevalence of CACS between those taking fibrates and propensity-matched controls (49.7 vs. 46.6%). When skeletal muscle mass was measured directly using cross-sectional imaging, patients on fibrates were found to have lost significantly less muscle area over time (-3.3 vs.-4.2%, p = 0.03). There was no difference in overall survival between groups.
CONCLUSION: Patients with NSCLC taking fibrates at the time of diagnosis lost less muscle area over time. In a secondary analysis, this change was not associated with a change in overall survival, though this study was likely underpowered for this analysis.

Keywords:  PPAR‐α; cachexia; fibrates; lung cancer; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.70016
Medicine (Baltimore). 2025 Aug 22. 104(34): e43985

The relationship between hemoglobin, albumin, lymphocyte, and platelet score and mortality in non-small cell lung cancer.

Mesut Buz, Mehmet İlhan Sesigüzel, Yunus Emre Özsaray, Attila Özdemir, Mahmut Talha Doğruyol, Riza Berk Çimenoğlu, Recep Demirhan.

  Non-small cell lung cancer (NSCLC) has a high mortality rate, emphasizing the need for reliable preoperative prognostic tools. Recent studies have focused on markers that reflect both inflammatory and nutritional status. This study aimed to evaluate the prognostic value of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score in predicting postoperative outcomes in NSCLC patients. This retrospective observational study included patients diagnosed with NSCLC who underwent curative surgery between January 1, 2019, and January 1, 2024. Preoperative HALP scores were calculated from routine blood tests to assess their potential as independent predictors of survival and long-term outcomes. The study cohort comprised 238 patients, divided into 2 groups: survivors (n = 153, 64.3%) and deceased patients (n = 85, 35.7%). The median HALP score was significantly lower in the deceased group (31.2) compared to survivors (52.3; P < .001). Follow-up duration was also significantly shorter in the deceased group (median 22 months) compared to survivors (median 34 months; P < .001). In the Cox univariate analysis, age ≥ 65 years (hazard ratio [HR] 2.02, 95% confidence intervals [CI] 1.32-3.1, P = .002), positive surgical margins (HR 3.04, 95% CI 1.61-5.76, P = .003), and low HALP scores (HR 5.17, 95% CI 3.33-8.03, P < .001) were significantly associated with decreased survival. However, in the multivariate analysis, positive surgical margins (HR 2.74, 95% CI 1.35-5.56, P = .005) and low HALP scores (HR 5.80, 95% CI 3.6-9.3, P < .001) remained independent predictors of decreased survival, while age ≥ 65 years did not retain significance. These findings suggest that positive surgical margins and low HALP scores are key prognostic factors for survival in NSCLC patients. The HALP score was identified as an independent predictor of postoperative mortality in NSCLC patients. Lower scores were significantly associated with higher mortality, indicating its potential use in both risk assessment and guiding postoperative management.

Keywords:  HALP score; mortality; non-small cell lung cancer

DOI:  https://doi.org/10.1097/MD.0000000000043985
Biomolecules. 2025 Aug 08. pii: 1144. [Epub ahead of print]15(8):

Hypoxia Exacerbates Inflammatory Signaling in Human Coronavirus OC43-Infected Lung Epithelial Cells.

Jarod Zvartau-Hind, Hassan Sadozai, Hateem Z Kayani, Animesh Acharjee, Rory Williams, Phillip Gould, Christopher A Reynolds, Bernard Burke.

  Cytokine storm (CS) is associated with poor prognosis in COVID-19 patients. Hypoxic signaling has been proposed to influence proinflammatory pathways and to be involved in the development of CS. Here, for the first time, the role of hypoxia in coronavirus-mediated inflammation has been investigated, using transcriptomic and proteomic approaches. Analysis of the transcriptome of A549 lung epithelial cells using RNA sequencing revealed 191 mRNAs which were synergistically upregulated and 43 mRNAs which were synergistically downregulated by the combination of human Betacoronavirus OC43 (HCoV-OC43) infection and hypoxia. Synergistically upregulated mRNAs were strongly associated with inflammatory pathway activation. Analysis of the expression of 105 cytokines and immune-related proteins using antibody arrays identified five proteins (IGFBP-3, VEGF, CCL20, CD30, and myeloperoxidase) which were markedly upregulated in HCoV-OC43 infection in hypoxia compared to HCoV-OC43 infection in normal oxygen conditions. Our findings show that COVID-19 patients with lung hypoxia may face increased risk of inflammatory complications. Two of the proteins we have identified as synergistically upregulated, the cytokines VEGF and CCL20, represent potential future therapeutic targets. These could be targeted directly or, based on the novel findings described here by inhibiting hypoxia signaling pathways, to reduce excessive inflammatory cytokine responses in patients with severe infections.

Keywords:  CCL20; COVID-19; HCoV-OC43; IGFBP3; VEGF; cytokine storm; hypoxia; inflammation

DOI:  https://doi.org/10.3390/biom15081144
Sci Rep. 2025 Aug 22. 15(1): 30840

Risk prediction model for overall survival in lung cancer based on inflammatory and nutritional markers.

Hongqi Zhou, Weiyun Jin, Lindi Li, Xiangwen Nie, Weiwei Wu, Ran Chen, Qizhen Xie, Haixia Wu, Weiwei Jiang, Min Tang, Jinhai Wang, Maoyuan Wang.

  This study aims to develop a multidimensional risk prediction model, identify characteristic inflammation-nutrition biomarkers, and optimize clinical decision-making. The study included 500 lung cancer patients diagnosed between October 2019 and October 2024 at a tertiary medical institution in Guiyang, China. The exposure variables included eight inflammation-nutrition biomarkers: neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), hemoglobin-albumin-lymphocyte-platelet score (HALP), prognostic nutritional index (PNI), hemoglobin-to-red cell distribution width ratio (HRR), and albumin-to-globulin ratio (ALB/GLB). The outcome variable was overall survival (OS). This study aimed to predict 1-year mortality rather than conduct traditional time-to-event survival analysis. All patients were followed until death or a uniform administrative censoring point.LASSO logistic regression was employed to model the outcome as a binary classification (death within 1 year: yes/no).This study employed a small-sample modeling approach, initially using LASSO regression for feature selection and dimensionality reduction, followed by variance inflation factor and collinearity screening for secondary feature selection. Finally, the Support Vector Machine-Recursive Feature Elimination (SVM-RFE) algorithm was used to optimize feature variables. The results showed that age, clinical stage, poor differentiation, ECOG PS 0-1, serum albumin level, LMR, HRR, and ALB/GLB were independent prognostic factors. Based on these factors, a lung cancer mortality risk prediction model was developed, and a corresponding web-based calculator was created, providing a practical tool to support clinical decision-making and personalized treatment strategies.

Keywords:  Healthy aging; Inflammation-Nutrition biomarkers; Lung cancer; Public health; Risk prediction model

DOI:  https://doi.org/10.1038/s41598-025-16443-1
Cancer Res. 2025 Aug 21.

Targeting ATP7A-Dependent Copper Metabolic Homeostasis Induces Cuproptosis and Suppresses the Progression of Mutant KRAS-Driven Lung Cancer.

Jian Zhao, Weijie Zhang, Yuanyuan Zeng, Di Lu, Chengkang Ma, Mengzhu Zhang, Xin Cai, Zhifan Huang, Hongli Yang, Jianjun Li, Jianjie Zhu, Jian-An Huang, Zeyi Liu.

Despite progress in tumor-targeted therapy, oncogenic KRAS remains a major challenge in treating lung adenocarcinoma (LUAD). In clinical practice, KRASG12C inhibitors have limited response rates and are associated with acquired drug resistance. Cuproptosis is a recently identified form of copper (Cu)-mediated cell death, and previous studies have revealed that Cu metabolism plays an important role in the development of KRAS-driven tumors. Here, we revealed the therapeutic value of the Cu ionophore elesclomol (ES) for treating KRASG12-mutant-driven LUAD. KRASG12-mutant LUAD cells relied on the Cu exporter ATP7A to maintain Cu homeostasis. ES induced in cellular Cu accumulation and cuproptosis by upregulating expression of the E3 ligase OSTM1, which interacted with the IRGY motif of ATP7A to promote ubiquitination and degradation. KRASG12D transgenic mice and lung cancer organoids (LCOs) derived from the mice were used to validate the therapeutic effects of ES and Cu in vivo and in vitro. These findings indicate that KRASG12-driven LUAD relies on ATP7A-mediated Cu metabolic homeostasis, which can be perturbed with ES as an effective treatment strategy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2558
Clin Cancer Res. 2025 Aug 25.

Multi-Omics and Single-Cell Insights Reveal a Lysophosphatidic Acid (LPA)-Mediated Resistant Mechanism to Third Generation EGFR-TKI in Non-Small Cell Lung Cancer.

Ruyun Gao, Ning Lou, Sheng Yang, Mengwei Yang, Guangyu Fan, Liyuan Dai, Le Tang, Jiarui Yao, Xiaohong Han, Yuankai Shi.

INTRODUCTION: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-sensitive-mutant non-small cell lung cancer (NSCLC). However, acquired resistance remains a significant challenge. This study investigates the metabolic mechanisms driving third-generation EGFR-TKI resistance.
METHODS: We conducted plasma metabolomics analysis on 216 longitudinal samples from 186 NSCLC patients enrolled in the clinical trial of rezivertinib (NCT03386955). Additionally, multi-omics profiling of rezivertinib-resistant cell lines, functional in vitro experiments, and single-cell RNA sequencing (scRNA-seq) analyses of 215 NSCLC patients were integrated to reveal underlying mechanisms.
RESULTS: Non-responder patients exhibited elevated glycerophospholipids and dysregulated lysophospholipid (LPL) metabolism. Unsupervised clustering identified two patient subgroups, with Cluster 1 (characterized by high LPL levels) associated with poorer survival (P = 0.022). Metabolite-based predictive model achieved robust performance (AUC: 0.7762 [training], 0.7485 [test]). Longitudinal analyses demonstrated LPLs and lysophosphatidic acid (LPA) accumulation during the resistance process. Integrated multi-omics analyses highlighted epithelial-mesenchymal transition (EMT) and glycerophospholipid reprogramming in rezivertinib-resistant cells. Functional assays confirmed that LPA promoted cell migration and invasion, and attenuated the efficacy of third-generation EGFR-TKI, while disruption of the LPA-LPAR signaling axis reversed LPA-mediated resistance. scRNA-seq identified an LPA-secreting malignant subset (cluster c4), characterized by enhanced EMT activation and extensive microenvironmental crosstalk through Wnt, TGF-β, and ECM signals.
CONCLUSIONS: Our study highlights the pivotal role of LPA-mediated signaling and metabolic reprogramming in third-generation EGFR-TKI resistance. Targeting LPA production or its downstream pathways may offer novel therapeutic strategies to overcome resistance. This study provides critical metabolic insights for managing EGFR-sensitive-mutant NSCLC.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0993
Transl Oncol. 2025 Aug 20. pii: S1936-5233(25)00227-X. [Epub ahead of print]61 102496

Disulfidptosis-associated gene signature predicts prognosis and radioresistance in NSCLC.

Jianmin Liu, Juan Wang, Jia Wang, Meng Wu, Jinming Yu, Dawei Chen.

   BACKGROUND: NSCLC has an extremely high mortality rate, and limitations exist in the efficacy of current therapeutic modalities and the choice of treatment strategies. Cells overexpressing cystine/glutamate transporter proteins and experiencing a glucose shortage could lead to NADPH deficiency and excessive disulfide buildup, causing stress responses and cell death, which affects patient's prognosis.
METHODS AND MATERIALS: Based on TCGA and GEO datasets, consensus clustering of NSCLC patients was performed to identify disulfidptosis-related genes and construct a prognostic model. The predictive ability of the model was validated in multiple datasets. Survival analysis, genomic mutations, and immune infiltration were used to characterize epigenetic alterations in different risk groups. Multiple radiotherapy-associated NSCLC datasets and radioresistant cell lines were employed to explore the relationship between disulfidptosis-related genes and radiotherapy.
RESULTS: We identified nine disulfidptosis-associated prognostic genes (DAPGs) and calculated the disulfidptosis-relevant risk score (DRRS). The risk groups showed a difference in prognosis, genomic mutations, and immune infiltration. CAFs and epithelial-mesenchymal transition significantly enriched in the high DRRS group. The prognostic model also effectively predicted the prognosis of patients receiving radiotherapy, and expression of DAPGs, especially KIF14, is strongly associated with DNA damage and repair, and high expression of KIF14 was observed in radioresistant cells.
CONCLUSIONS: Our findings imply that a prognostic model related to disulfidptosis could distinguish the prognostic differences among patients, allowing for more personalized treatment strategies. The mechanisms of KIF14 may provide a basis for combating radioresistance and a better understanding of the interaction between disulfidptosis and radiotherapy.

Keywords:  Disulfidptosis; Immune infiltration; NSCLC; Prognostic model; Radioresistance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2025.102496
Free Radic Res. 2025 Aug 30. 1-13

Pseudohypoxia induced by iron chelator activates tumor immune response in lung cancer.

Yusuke Hamada, Toshiaki Ohara, Yuehua Chen, Manato Terada, Yuze Wang, Hotaka Kawai, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa.

  Hypoxia-inducible factor (HIF) signaling plays a critical role in immune cell function. Pseudohypoxia is characterized as iron-mediated stabilization of HIF-1α under normoxic conditions, which can be induced by iron chelators. This study explored whether iron chelators exert antitumor effects by enhancing tumor immune responses and elucidating the underlying mechanisms. The iron chelators Super-polyphenol 10 (SP10) and Deferoxamine (DFO) were used to create iron-deficient and pseudohypoxia conditions. Pseudohypoxia induced by iron chelators stimulates IL-2 secretion from T cells and from both human and murine nonsmall cell lung cancer (NSCLC) cell lines (A549, PC-3, and LLC). Administration of SP10 reduced tumor growth when LLC tumors were implanted in C57BL/6 mice; however, this was not observed in immunodeficient RAG1-deficient C57BL/6 mice. SP10 itself did not directly inhibit LLC cells proliferation in vitro, suggesting an activation of the tumor immune response. SP10 synergistically enhanced the efficacy of PD-1 antibody therapy in lung cancer by increasing the number of tumor-infiltrating lymphocytes (TILs). In conclusion, iron chelation-induced pseudohypoxia activates tumor immune responses by directly upregulating HIF-1α, augmenting T cell function, and inducing IL-2 secretion from T cells, and cancer cells, thereby amplifying the immune efficacy of the PD-1 antibody in lung cancer treatment.

Keywords:  Lung cancer; hypoxia-inducible factor; immune checkpoint inhibitors; iron

DOI:  https://doi.org/10.1080/10715762.2025.2551030