bims-meluca 2026-10-18 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–10–18
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Metabolic signature of phosphoethanolamine and arginine pathways predicts prognosis and immunotherapy resistance in lung adenocarcinoma.
SGLT2-mediated glucose uptake defines early metabolic reprogramming in lung adenocarcinoma.
Metabolic alterations and redox homeostasis in ferroptosis: emerging mechanisms and therapeutic implications.
LKB1 promotes lung adenocarcinoma cell senescence by suppressing the O-GlcNAc glycosylation-mediated activation of telomerase.
Epigallocatechin gallate and thermal cycling‑stimulation synergistically promote apoptosis in A549 cells via endoplasmic reticulum stress‑induced calcium ion dysregulation and oxidative stress.
ATF4 and SLC7A11 as biomarkers predicting progression and prognosis in lung adenocarcinoma.

Transl Cancer Res. 2026 Sep 30. 15(9): 706

Metabolic signature of phosphoethanolamine and arginine pathways predicts prognosis and immunotherapy resistance in lung adenocarcinoma.

Tao Wang, Hongwei Li, Fei Ding.

   Background: Metabolic reprogramming is a hallmark of lung adenocarcinoma (LUAD). However, the prognostic significance of phosphoethanolamine (pEtn) and arginine metabolism-related genes remains poorly defined. This study aimed to develop and externally validate a pEtn- and arginine metabolism-related gene signature for predicting prognosis in LUAD and to characterize its associations with tumor biology, immune response, and therapeutic sensitivity.
Methods: We analyzed transcriptomic data from The Cancer Genome Atlas (TCGA) LUAD (TCGA-LUAD, n=514) and independent Gene Expression Omnibus (GEO) cohorts. Candidate genes were identified from Molecular Signatures Database (MSigDB) gene sets, followed by differential expression, Cox regression, and protein-protein interaction (PPI) analyses. An 18-gene metabolic signature was constructed using least absolute shrinkage and selection operator (LASSO) regression and validated across three external datasets. Functional enrichment, immune infiltration profiling, Tumor Immune Dysfunction and Exclusion (TIDE) analysis, and drug sensitivity prediction, Cancer Therapeutics Response Portal (CTRP), and Genomics of Drug Sensitivity in Cancer (GDSC) were performed to explore biological and therapeutic implications.
Results: We identified 114 metabolism-related genes, of which 27 were significantly associated with overall survival (OS). An 18-gene prognostic signature stratified patients into high- and low-risk groups, with high-risk patients showing significantly poorer survival [TCGA: hazard ratio (HR) =2.81, P<0.001; external validation: HR 2.60-3.24, all P<0.01]. High-risk tumors were enriched in cell cycle, glycolysis, and epithelial-mesenchymal transition (EMT) pathways, and exhibited elevated but dysfunctional CD8+ T cell infiltration, consistent with immune exclusion and reduced immunotherapy response. Drug sensitivity analysis suggested that high-risk patients may benefit from dasatinib, lovastatin, irinotecan, and talazoparib.
Conclusions: An 18-gene metabolic signature demonstrates robust prognostic value in LUAD, linking metabolic reprogramming with tumor aggressiveness, immunotherapy resistance, and drug vulnerability. This model provides a potential tool for risk stratification and personalized treatment.

Keywords:  Lung adenocarcinoma (LUAD); arginine metabolism; immunotherapy resistance; phosphoethanolamine metabolism (pEtn metabolism); prognostic signature

DOI:  https://doi.org/10.21037/tcr-2026-1553
Cancer Prev Res (Phila). 2026 Oct 14.

SGLT2-mediated glucose uptake defines early metabolic reprogramming in lung adenocarcinoma.

Katherine A Ortmeyer, Kelly Anne McGovern, Lydia Chen, Kevin Guo, Jeffrey Huang, Michael Brown, Ryan Krouse, Jake Mlakar, Paul Zhang, Sunil Singhal.

The metabolic reprogramming taking place during early lung adenocarcinoma (LUAD) progression remain poorly understood. While early-stage LUAD frequently demonstrates low 18F-2-fluorodeoxyglucose (18FDG) uptake on positron emission tomography (PET), it is unclear whether this reflects metabolic quiescence or alternative glucose utilization pathways. We hypothesized that early lesions are metabolically active but preferentially utilize sodium-glucose cotransporter 2 (SGLT2), a non-canonical glucose transporter with low 18FDG affinity. This study investigates metabolic activity in early-stage LUAD and glucose transporter expression patterns across the adenocarcinoma spectrum. LDH, SGLT2 and GLUT1 expression were evaluated by immunohistochemistry in human lung cancers and compared with normal lung and benign inflammation. Expression levels were correlated with structural and radiologic features including tumor size, invasion, histology, radiographic features and PET avidity. Glycolysis was elevated in premalignant and early LUAD as indicated by LDH expression. SGLT2 was highly expressed in preinvasive and minimally invasive LUAD compared to normal lung and invasive tumors. Conversely, GLUT1 was upregulated in invasive, high-grade tumors. Radiographically, SGLT2 expression was associated with subsolid nodules and low PET avidity, while GLUT1 expression was higher in nodules with a solid component and high 18FDG avidity. Notably, SGLT2 was not elevated in inflammatory lesions compared to normal lung, unlike GLUT1, which was frequently upregulated in inflammation. Early lung adenocarcinoma lesions exhibit aerobic glycolysis despite low FDG avidity and preferentially utilize SGLT2-mediated glucose uptake. These findings highlight a distinct metabolic profile in early LUAD and underscore the need for alternative imaging modalities to enhance the detection of early lesions.

DOI: https://doi.org/10.1158/1940-6207.CAPR-26-0170
Arch Med Sci. 2026 ;22(4): 2231-2249

Metabolic alterations and redox homeostasis in ferroptosis: emerging mechanisms and therapeutic implications.

Mirjana Macvanin, Dušan Spasić, Sanja Gluscevic, Tatjana Srdić-Rajić, Aleksandra Klisic.

  Ferroptosis is a programmed cell death characterized by excessive, iron-dependent accumulation of membrane lipid peroxides due to insufficient glutathione-dependent antioxidant defense. It is influenced by the metabolism of amino acids, lipids, and iron, and occurs in conditions of decreased glutathione peroxidase 4 (GPX4) activity. The increased polyunsaturated fatty acid (PUFA) content in membrane phospholipids is associated with cellular hypersusceptibility to ferroptosis. In contrast, incorporation of monounsaturated fatty acids may protect cells against ferroptotic cell death. Cellular sensitivity to ferroptosis is additionally influenced by glutamine catabolism and the xc-system-mediated import of cystine, which modulate glutathione production, and by elevated iron levels, which lead to the buildup of reactive oxygen species (ROS) that attack membrane-localized PUFAs. This review focuses on recent findings of perturbed metabolic processes in cancer that create a high iron demand and an altered lipid composition, thereby predisposing cells to ferroptosis. We analyze the therapeutic potential of pharmacological agents that can selectively trigger ferroptosis in tumor cells.

Keywords:  GPX4; cancer therapeutics; ferroptosis; glutathione metabolism; iron metabolism; lipid metabolism; redox homeostasis

DOI:  https://doi.org/10.5114/aoms/225096
Front Pharmacol. 2026 ;17 1952846

LKB1 promotes lung adenocarcinoma cell senescence by suppressing the O-GlcNAc glycosylation-mediated activation of telomerase.

Liting Gu, Mingdi Liu, Yunkuo Li, Honglan Zhou, Yishu Wang, Zhi-Xiang Xu.

   Background: Telomeres are crucial for maintaining genomic integrity and stability, making them promising anticancer therapy targets. O-GlcNAc glycosylation is unique and involved in most cellular functions. In most cancers, there is a positive correlation between the degree of tumor malignancy and O-GlcNAc glycosylation levels. However, the relationship between O-GlcNAc glycosylation and telomerase in lung adenocarcinoma remains unclear. We thus investigated the O-GlcNAc-mediated regulation of telomerase activity.
Methods: Protein and mRNA expression levels were detected via western blotting and RT-qPCR, respectively. Telomerase activity, telomere length, and telomere-induced injury foci were detected using telomeric repeat amplification protocol, telomere restriction fragment, and Q-FISH assays, respectively. Cell senescence and proliferation were detected using SA-β-gal staining and EdU assays. IHC and H&E staining were used to detect p53, PCNA, and BCL-2 protein levels in the transplanted tumor tissues and their effects on organs in transplanted tumor-bearing mice.
Results: Our findings revealed that LKB1 reduces the overall activity of O-GlcNAcylation and telomerase, resulting in the shortening of telomeres, increased senescence and apoptosis, and decreased tumor cell growth. Insights into the underlying mechanisms have shown that LKB1-AMPK influence the hexosamine biosynthesis pathway (HBP), potentially via the phosphorylation of GFAT1. In vivo studies revealed that using both O-GlcNAc and telomerase inhibitors together led to the senescence of tumor cells and hindered their growth, suggesting a viable treatment method for clinical lung adenocarcinoma.
Discussion: O-GlcNAc glycosylation promotes telomerase activity and inhibits tumor cell senescence, thereby maintaining telomere lengths in lung adenocarcinoma tumor cells. LKB1 inhibits telomerase activity via the HBP, which may depend on GFAT1 phosphorylation by LKB1. Telomerase inhibitors coupled with O-GlcNAc inhibitors significantly inhibit tumor growth in mice, suggesting clinical lung adenocarcinoma treatment strategies.

Keywords:  LKB1; O-GlcNAc glycosylation; cellular senescence; lung adenocarcinoma; telomerase

DOI:  https://doi.org/10.3389/fphar.2026.1952846
Mol Med Rep. 2026 Dec;pii: 332. [Epub ahead of print]34(6):

Epigallocatechin gallate and thermal cycling‑stimulation synergistically promote apoptosis in A549 cells via endoplasmic reticulum stress‑induced calcium ion dysregulation and oxidative stress.

Fang-Tzu Hsu, Hsu-Hsiang Liu, Yi Kung, Chieh-Jou Lin, Chih-Yu Chao.

  Non‑small cell lung cancer (NSCLC), as the predominant subtype of lung cancer, presents a considerable clinical challenge due to its high rates of recurrence and the significant adverse effects associated with conventional therapeutic modalities. In response to these challenges, the present study has explored the combined anticancer effects of epigallocatechin gallate (EGCG) together with thermal cycling‑stimulation (TCS). The findings obtained demonstrated that the combination of EGCG and TCS led to a synergistic decrease in the viability of A549 and NCI‑H460 NSCLC cells, whereas IMR‑90 normal lung fibroblasts exhibited minimal cytotoxic effects. Further investigations revealed that EGCG could mitigate the TCS‑induced upregulation of the heat shock proteins (HSPs) HSP70 and HSP105, whereas the expression levels of proteasome subunits were concurrently decreased. These alterations were accompanied by the disruption of proteostasis, and also by the activation of endoplasmic reticulum (ER) stress‑associated pathways. Furthermore, pharmacological inhibition studies suggested a mutual interplay between inositol 1,4,5‑trisphosphate receptor‑mediated ER Ca2+ release and an excessive production of reactive oxygen species, ultimately causing the cells to undergo mitochondrial apoptosis. In summary, the present study has shown that the combined treatment of EGCG and TCS reduces the required dosage of EGCG, while also attenuating TCS‑induced heat shock responses. Consequently, the present study offers a novel and promising in vitro proof‑of‑concept strategy for treating NSCLC.

Keywords:  EGCG; NSCLC; combination treatment; hyperthermia

DOI:  https://doi.org/10.3892/mmr.2026.14043
Front Oncol. 2026 ;16 1969897

ATF4 and SLC7A11 as biomarkers predicting progression and prognosis in lung adenocarcinoma.

Yanjie Liu, Dongli Guo, Daojuan Li, Jing Jin.

   Background: Lung adenocarcinoma (LUAD) is the most prevalent subtype of non-small cell lung cancer, yet reliable biomarkers for stratifying early-stage patients at high risk of progression and poor prognosis remain limited.
Methods: We enrolled 168 LUAD patients who underwent surgery at The Fourth Hospital of Hebei Medical University. ATF4 and SLC7A11 expressions were assessed by immunohistochemistry. Associations with clinicopathological features were evaluated by χ²/Fisher's exact tests; univariate and multivariate Cox regression analyses of overall survival (OS) and metastasis-free survival (MFS) were performed, and model discrimination was quantified by the concordance index (C-index).
Results: ATF4 was nuclear-positive in 55.4% of tumors, and SLC7A11 was cytoplasmic-positive in 59.5% of tumors. Neither ATF4 nor SLC7A11 was positively expressed in the stromal cells. The expression of ATF4 and SLC7A11 in tissues with pathological necrosis was enhanced. Both ATF4 and SLC7A11 correlated with aggressive features (more aggressive pathological subtypes with malignant potential, advanced clinical stage, lymph node metastasis, poor differentiation, pleural invasion, and pathological necrosis). ATF4 expression was also associated with lymphatic/vascular invasion. ATF4 (HR = 1.533, 95% CI, 1.040-2.259; P = 0.031) and SLC7A11 (HR = 1.527, 95% CI, 1.013-2.303; P = 0.043) were both independent prognostic factors for OS. As a combined indicator, ATF4 and SLC7A11 can enhance the C-index of the prognostic prediction model, and either positive for ATF4 or SLC7A11 have the highest C-index, regardless of whether it is for OS or MFS.
Conclusion: ATF4/SLC7A11 are clinically useful prognostic biomarkers in LUAD. Either ATF4- or SLC7A11-positive expression appears to yield enhanced predictive value and may help identify high-risk patients for intensified surveillance.

Keywords:  ATF4; SLC7A11; lung adenocarcinoma; prognosis; prognostic prediction model

DOI:  https://doi.org/10.3389/fonc.2026.1969897