bims-meluca 2026-08-09 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–08–09
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Mannose supports lung cancer metabolism during glycolytic limitation.
The prognostic value of cachexia index in patients with lung cancer treated with immune checkpoint inhibitors: a propensity score matching analysis.
The ER stress-autophagy axis in cancer-induced muscle wasting: Unveiling the IRE1α/XBP1 pathway as a therapeutic target.
A Glutathione Metabolism-Related Transcriptomic Signature for Prognostic Assessment and Biological Characterization of Lung Adenocarcinoma.
Two stress-responsive kinases suppress ferroptosis by activating antioxidant programs under mild oxidative stress.
ATF4/SCO2 Inhibits Ferroptosis in Lung Cancer Through Activating the MAPK Signaling Pathway.
Tumoral extracellular vesicles and particles reprogram interstitial macrophages in the lung to promote vascular permeability and metastasis.
Metabolic control of ferroptosis in cancer: lipid dependencies as therapeutic vulnerabilities.

EMBO Rep. 2026 Aug 07.

Mannose supports lung cancer metabolism during glycolytic limitation.

Theresa Haitzmann, Niklas B Thompson, Hardik Shah, Katharina Schindlmaier, Joseph Jelwan, Thomas O Eichmann, Nia G Hammond, Maia G Clare, Robert B Cameron, Brandon Faubert, Katharina Leithner.

Cancer cells frequently show elevated glucose consumption to support proliferation and survival. This led to the assumption that glycolytic inhibitors could be effective in cancer treatment. However, barriers to clinical implementation remain. Adaptive strategies, such as metabolizing alternative nutrients, may play a role. Here, we investigated the use of an understudied sugar, mannose, in lung cancer cells and xenografts. Stable isotope tracing reveals enhanced contribution of mannose to GDP-mannose and GDP-fucose, key glycosylation precursors, upon treatment with the glycolytic inhibitor 2-deoxyglucose (2-DG) or glucose starvation in vitro. Mannose restores the glucose-withdrawal-induced decrease of GDP-mannose and GDP-fucose pools, and partially rescues proliferation upon 2-DG treatment or glucose deprivation. 13C6-mannose infusion in patient-derived xenograft mice reveals a considerable contribution of mannose to GDP-mannose and GDP-fucose in tumors, which is further enhanced by 2-DG. In normal lungs, the pathway is only partially active. Mannose is also shuttled towards glycolysis in lung tumors in vivo and glucose-deprived cells in vitro. In conclusion, mannose utilization for glycosylation precursor synthesis represents an adaptive strategy in lung cancer cells under metabolic stress.

DOI: https://doi.org/10.1038/s44319-026-00874-6
Front Nutr. 2026 ;13 1810531

The prognostic value of cachexia index in patients with lung cancer treated with immune checkpoint inhibitors: a propensity score matching analysis.

Huachi Li, Mengxing Tian, Wen Wang, Qian Han, Xin Jin, Xiantian Xu.

   Background: Cancer cachexia index (CXI) is a potential tool for cancer cachexia diagnosis in patients with lung cancer. However, the predictive value of the CXI for clinical outcomes in patients with lung cancer receiving immune checkpoint inhibitors (ICIs) remains unclear. This study aimed to investigate the role of the CXI in predicting overall survival in patients with lung cancer undergoing ICIs.
Methods: A single-center retrospective study was conducted, enrolling 119 patients with lung cancer who received ICIs. The clinical, laboratory, abdominal computed tomography (CT) images and follow-up data before immunotherapy were collected for all participants. The CXI was calculated by integrating the CT-derived skeletal muscle index (SMI) at the third lumbar vertebra level with serum albumin and the neutrophil-to-lymphocyte ratio. Kaplan-Meier survival analysis was used to compare overall survival (OS) differences between patients with a low CXI and those with a high CXI. Univariate and multivariable Cox proportional hazards regression models were applied to identify independent prognostic factors for OS. Propensity score matching (PSM) was performed to minimize selection bias, and a nomogram was constructed based on the CXI.
Results: Kaplan-Meier survival curves showed that patients with a low CXI had significantly lower 3-year OS rate than those with a high CXI in both the total cohort (24.6% vs. 65.1%, p < 0.001) and the PSM-matched cohort (23.2% vs. 74.2%, P = 0.001). Multivariable Cox regression analysis identified a low CXI as negative prognostic factor for OS in patients with lung cancer receiving ICIs in the total cohort (hazard ratio [HR] = 3.11; 95% confidence interval [CI]: 1.52-6.37; p < 0.001) and the PSM cohort (HR = 5.55; 95% CI: 1.86-16.61; p < 0.001). Gender, age, disease stage, smoking status, nutritional risk, BMI, pathology, type of ICIs, surgery and CXI were used to develop the nomogram. Additionally, the CXI was found to correlate with the SMI with a statistically significant weak to moderate positive correlation (ρ = 0.328; p = 0.0003).
Conclusion: In patients with lung cancer receiving ICIs, CXI is an independent prognostic factor for OS. It may serve as a valuable clinical tool for assessing cancer cachexia in lung cancer patients undergoing immunotherapy.

Keywords:  cachexia index; cancer cachexia; immune checkpoint inhibitors; lung cancer; overall survival

DOI:  https://doi.org/10.3389/fnut.2026.1810531
Biochim Biophys Acta Rev Cancer. 2026 Aug 03. pii: S0304-419X(26)00148-4. [Epub ahead of print] 189676

The ER stress-autophagy axis in cancer-induced muscle wasting: Unveiling the IRE1α/XBP1 pathway as a therapeutic target.

Guanran Ding, Wang Yang, Yixin Zhao, Xiangliang Liu, Jiuwei Cui.

  Cancer cachexia is a multifactorial syndrome of progressive skeletal muscle wasting and functional decline that affects 50-80% of patients with advanced malignancies, frequently overlaps with sarcopenia, and contributes to 22-30% of cancer-related deaths. Effective therapies remain lacking, in part because the driving mechanisms are incompletely understood. Systemic inflammation-particularly interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-has long been considered central to muscle wasting, yet cytokine-targeted trials have shown limited efficacy, prompting investigation of additional pathways. Among these, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as candidates, and this review focuses specifically on the IRE1α/XBP1 branch. The rationale rests on three observations from recent preclinical studies: XBP1s activity is increased in cachectic muscle; XBP1s occupies regulatory regions of autophagy-lysosome and ubiquitin-proteasome genes, a direct transcriptional link to protein degradation that distinguishes it from the translation-attenuating PERK and folding-oriented ATF6 branches; and genetic or pharmacological suppression of IRE1α/XBP1 attenuates wasting in these models. We examine how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory (JAK-STAT3, NF-κB) and metabolic (mitochondrial dysfunction, fatty acid metabolism) networks; the evidence across cancer models and clinical contexts; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine. We frame the ER stress-autophagy axis as a mechanistically plausible, potentially tractable therapeutic target that requires further cross-model and clinical validation.

Keywords:  Arginine; Autophagy; Cancer cachexia; Endoplasmic reticulum stress; IRE1α; Muscle wasting; Therapeutic target; Ubiquitin-proteasome system; XBP1

DOI:  https://doi.org/10.1016/j.bbcan.2026.189676
Cancer Inform. 2026 ;25 11769351261476162

A Glutathione Metabolism-Related Transcriptomic Signature for Prognostic Assessment and Biological Characterization of Lung Adenocarcinoma.

Zhengzuo Sheng, Siyu Chen, Su Chen.

   Background: Glutathione metabolism plays an important role in redox homeostasis, oxidative stress responses, and metabolic adaptation in cancer. However, its prognostic significance in lung adenocarcinoma (LUAD) remains incompletely understood. This study aimed to develop a glutathione metabolism-related prognostic signature and investigate its associations with immune characteristics, genomic alterations, and biological pathways in LUAD.
Methods: Transcriptomic, clinical, and somatic mutation data from TCGA-LUAD were analyzed, and GSE50081 was used as an independent validation cohort. Glutathione metabolism-related genes were identified through differential expression and Cox regression analyses, followed by least absolute shrinkage and selection operator (LASSO) Cox regression to construct a prognostic signature. Survival analysis, time-dependent receiver operating characteristic (ROC) analysis, Cox regression, immune infiltration analysis, Gene Set Enrichment Analysis (GSEA), mutation profiling, tumor mutation burden (TMB) analysis, and drug-sensitivity prediction were subsequently performed.
Results: A glutathione metabolism-related signature stratified patients into high- and low-risk groups with significantly different overall survival in both the TCGA training cohort and the GSE50081 validation cohort. The risk score remained an independent prognostic factor in multivariable Cox regression analysis. High-risk tumors exhibited reduced B-cell and dendritic-cell infiltration, enrichment of cell-cycle- and metabolism-related pathways, higher frequencies of TP53 and KEAP1 mutations, and elevated tumor mutation burden. Computational drug-sensitivity analysis identified differences in predicted responses to several therapeutic agents between risk groups.
Conclusions: The proposed glutathione metabolism-related signature demonstrated prognostic value in both training and validation cohorts and was associated with immune characteristics, pathway enrichment patterns, genomic alterations, and tumor mutation burden in LUAD. These findings provide additional insights into glutathione metabolism-related heterogeneity in LUAD and warrant further biological and clinical validation.

Keywords:  drug sensitivity; glutathione metabolism; lung adenocarcinoma; prognostic signature; tumor microenvironment; tumor mutation burden

DOI:  https://doi.org/10.1177/11769351261476162
Signal Transduct Target Ther. 2026 Aug 03. pii: 306. [Epub ahead of print]11(1):

Two stress-responsive kinases suppress ferroptosis by activating antioxidant programs under mild oxidative stress.

Yumiko Fujikawa, Hirotatsu Imai, Tetsuo Onuki, Kouji Hoshino, Marco A De Velasco, Kazuhiko Matsuo, Hitomi Kurosawa, Kyoko Aoyagi, Hiroko Hirose, Yoshie Nakamura, Akiko Uchiyama, Kae Suzuki, Mariko Mizuguchi, Hidehisa Takahashi, Hiroyuki Osada, Noritaka Kagaya, Kazuo Shin-Ya, Hiroyuki Satofuka, Yukinari Kato, Hidehito Kuroyanagi, Daisuke Utsumi, Kenzo Takahashi, Takashi Nakayama, Hirotsugu Uemura, Hiroji Uemura, Minoru Yoshida, Shigeo Ohno, Akio Yamashita.

Cancer cells maintain chronically elevated levels of reactive oxygen species (ROS) while relying on robust antioxidant programs to preserve redox homeostasis and viability. Although therapeutic strategies that disrupt this balance to induce lethal oxidative stress and ferroptosis have emerged as promising anticancer approaches, the upstream signaling mechanisms that constrain ROS accumulation under physiologically relevant stress conditions remain incompletely understood. Here, we identify the stress-responsive kinases SMG1 and DNA-dependent protein kinase (DNA-PK) as functionally redundant regulators of redox homeostasis and ferroptosis resistance. Genetic or pharmacological inhibition of either kinase triggers ferroptotic cell death, accompanied by marked accumulation of total ROS, ferrous iron, and lipid hydroperoxides. Mechanistically, under mild oxidative stress, SMG1 and DNA-PK cooperatively phosphorylate the central antioxidant transcription factor NRF2 at serine 13 and serine 40, weakening its interaction with the negative regulator KEAP1 and promoting NRF2 accumulation and transcriptional activation. Transcriptomic profiling of de novo mRNAs revealed that inhibition of either kinase is sufficient to suppress NRF2-driven antioxidant gene expression. In contrast, excessive oxidative stress overrides this pro-survival pathway and redirects signaling toward anti-survival responses mediated by ATF4, ATM-CHK2, and JNK/p38 pathways. Collectively, these findings uncover a previously unrecognized SMG1/DNA-PK-NRF2 signaling axis that functions as a redox stress-intensity-dependent switch governing cell fate decisions between antioxidant adaptation and ferroptotic death. Targeting this axis may represent a promising therapeutic strategy for cancer treatment.

DOI: https://doi.org/10.1038/s41392-026-02892-1
J Biochem Mol Toxicol. 2026 Aug;40(8): e71054

ATF4/SCO2 Inhibits Ferroptosis in Lung Cancer Through Activating the MAPK Signaling Pathway.

Liang Yu, Sheng Zhang, Jinxi He, Bo Ma, Xuyang Song, Rui Qiu, Bo Yu.

  Ferroptosis is a specific cell death form resulting from the iron-dependent lipid peroxidation, exhibiting an essential role in cancer progression. The purpose of this study was to explore the underlying mechanism of ferroptosis in lung cancer. The mRNA and protein expression levels were examined via real-time quantitative PCR and Western blotting. Cell malignant behaviors were assessed using cell counting kit-8 (CCK-8) assay, transwell assay, and flow cytometry. Ferroptosis was determined using the indicators lipid reactive oxygen species (ROS), glutathione (GSH), and Fe2+. Dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed for binding analysis between activating transcription factor 4 (ATF4) and synthesis of cytochrome c oxidase 2 (SCO2). Associated proteins in mitogen-activated protein kinases (MAPK) signaling pathway were measured by Western blotting. A mouse model was established by implanting lung cancer cells for in vivo research. Lung cancer samples and cells exhibited high expression of SCO2. SCO2 downregulation restrained lung cancer cell growth by inducing ferroptosis. ATF4 was an up-regulated gene in lung cancer, and it elevated SCO2 expression by binding to the promoter of SCO2. ATF4 knockdown repressed cell proliferation and migration while facilitating apoptosis and ferroptosis by down-regulating SCO2. Inhibition of ATF4/SCO2 inactivated the MAPK signaling pathway. ATF4-mediated SCO2 promoted lung tumorigenesis in vivo. This study manifested that ATF4 controlled SCO2 to suppress ferroptosis by activating the MAPK pathway, thus contributing to lung cancer development.

Keywords:  activating transcription factor 4; ferroptosis; lung cancer; mitogen‐activated protein kinase pathway; synthesis of cytochrome c oxidase 2

DOI:  https://doi.org/10.1002/jbt.71054
Nat Cancer. 2026 Aug 05.

Tumoral extracellular vesicles and particles reprogram interstitial macrophages in the lung to promote vascular permeability and metastasis.

Shani Dror, Inbal Wortzel, Serena Lucotti, Yura Seo, Jianlong Li, Lee Shaashua, Irina Matei, Nancy Boudreau, Haiying Zhang, Maider Astorkia-Amiama, Doron Betel, Han Sang Kim, Jai Prakash, Jacqueline Bromberg, David Lyden.

The mechanisms by which tumor-derived extracellular vesicles and particles (EVPs) promote vascular permeability during premetastatic niche formation remain unclear. Here, we show that tumor EVPs rapidly induce vascular leakiness within 1 h of administration in female mice, creating a permissive environment that enhances metastatic seeding. Rather than acting directly on endothelial cells, EVPs activate NF-κB and JAK-STAT signaling in interstitial macrophages, leading to IL-6 secretion and increased vascular permeability. Interstitial macrophage depletion markedly reduces EVP-induced vascular leakiness and metastasis. We identify extracellular vesicle-associated integrin α5 (ITGα5) as a major functional determinant of this process, promoting macrophage activation and IL-6 secretion without affecting EVP uptake. EVPs derived from colorectal cancer tumors with high ITGα5 similarly induce macrophage IL-6 secretion and vascular permeability. Together, these findings define an EVP-macrophage-IL-6 axis that drives vascular permeability during premetastatic niche formation and identify EVP-associated ITGα5 as a key mediator of metastatic progression and a potential therapeutic target.

DOI: https://doi.org/10.1038/s43018-026-01209-z
Front Oncol. 2026 ;16 1872103

Metabolic control of ferroptosis in cancer: lipid dependencies as therapeutic vulnerabilities.

Anna Di Dio, Gerardina Smaldone, Valeria Napolitano, Alessia Bertamino, Isabel M Gomez-Monterrey.

  Ferroptosis is an iron-dependent form of regulated cell death driven by the accumulation of peroxidized phospholipids in cellular membranes. In cancer, susceptibility to ferroptosis is not fixed but instead reflects a dynamic metabolic state shaped by lipid remodeling programs that determine membrane composition, oxidative liability, and the capacity to detoxify lipid peroxides. Tumor cells rewire fatty acid synthesis, desaturation, esterification, storage, sterol metabolism, and ether phospholipid remodeling to alter the abundance and distribution of oxidizable phospholipids and thereby shift their ferroptotic threshold. Polyunsaturated fatty acid-rich membrane phospholipids and di-polyunsaturated phospholipids promote lipid peroxidation and ferroptosis sensitivity, whereas monounsaturated fatty acids, lipid-droplet sequestration, 7-dehydrocholesterol, membrane-bound O-acyltransferase domain-containing 1 and 2, and antioxidant defense systems including glutathione peroxidase 4, ferroptosis suppressor protein 1, and the GTP cyclohydrolase 1-tetrahydrobiopterin pathway suppress ferroptotic death. Therapy-resistant, mesenchymal-like, and drug-tolerant persister states often display elevated oxidative stress together with increased dependence on lipid peroxide detoxification, whereas cancer stem cell-like states can remain either buffered or vulnerable depending on context. Here, we synthesize how lipid-state remodeling, tumor genotype, cell-state plasticity, and microenvironmental cues position tumors along a functional ferroptotic threshold, and we discuss how integrated lipidomic, transcriptional, and state-associated biomarkers may support biomarker-guided ferroptosis-based strategies in precision oncology.

Keywords:  ACSL4; FSP1; GPx4; MBOAT1/2; drug-tolerant persister cells; ferroptosis; lipid metabolism; lipid peroxidation

DOI:  https://doi.org/10.3389/fonc.2026.1872103