bims-meluca 2026-06-07 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–06–07
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Prognostic impact of weight loss during first-line chemotherapy in extensive-disease small cell lung cancer.
PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis.
Targeting GSTZ1 sensitizes KRAS G12C-mutant lung cancer cells by overcoming glutathione and glycolysis pathway rewiring.
GFPT2 upregulation predicts poor prognosis and is associated with TGF-β/Smad activation in lung adenocarcinoma.
MTHFR functions as a metabolic checkpoint in NSCLC through SLC25A26-mediated SHMT2 inhibition.
Novel Long-Acting Ghrelin Analogue PEP-064 Restores Energy Balance in C26 and Lewis Lung Carcinoma-Induced cachexia in Mice.
Lactate-activated astrocytes promote NSCLC brain metastasis through extracellular vesicle-mediated miR-8085/TRIM67/ELK1 signaling axis.
Exploring hypoxia-related genes as prognostic indicators in lung adenocarcinoma.

Support Care Cancer. 2026 Jun 02. pii: 598. [Epub ahead of print]34(6):

Prognostic impact of weight loss during first-line chemotherapy in extensive-disease small cell lung cancer.

Toshiya Fujisaki, Tateaki Naito, Satomi Kumaki, Shunichi Kataoka, Shin Saito, Suguru Matsuda, Haruki Kobayashi, Ryo Ko, Kazushige Wakuda, Akira Ono, Haruyasu Murakami, Toshiaki Takahashi, Hirotsugu Kenmotsu.

   PURPOSE: The adverse prognostic impact of cancer cachexia is well recognized. We aimed to evaluate the prognostic impact of weight loss during first-line platinum-based chemo(immuno)therapy in patients with extensive-disease small-cell lung cancer (ED-SCLC).
METHODS: We retrospectively reviewed 187 of 346 ED-SCLC patients (54%) treated between 2009 and 2021, and collected body weight at three time points: 6 months before, at the start of the first cycle, and at the beginning of the third cycle of initial chemotherapy. Based on pretreatment cachexia defined according to the Fearon criteria (weight loss > 5% or > 2% with BMI < 20 kg/m2 within 6 months) and > 2% weight loss from the start of chemotherapy to the beginning of the third cycle, we classified patients into four groups: those without weight loss both before and during chemotherapy (n = 75) (non-weight-loss group), those without weight loss before but with weight loss during chemotherapy (n = 34), those with weight loss before but not during chemotherapy (n = 46), and those with weight loss both before and during chemotherapy (n = 32). We evaluated survival outcomes and gastrointestinal toxicities during the first two cycles.
RESULTS: Median overall survival (OS) differed significantly among the groups (p = 0.020), with the non-weight-loss group showing more favorable survival than the other groups (adjusted hazard ratios, 1.51-1.65; all p ≤ 0.05). The non-weight-loss group experienced fewer grade ≥ 2 anorexia and nausea/vomiting events during the first two cycles.
CONCLUSIONS: In patients with ED-SCLC, the absence of weight loss before and during chemotherapy was associated with longer OS and fewer gastrointestinal toxicities. These findings underscore the importance of early supportive care to prevent weight loss, including proactive management of gastrointestinal toxicities during chemotherapy.

Keywords:  Cachexia; Prognosis; Small-cell lung carcinoma; Weight loss

DOI:  https://doi.org/10.1007/s00520-026-10840-6
Cell Death Dis. 2026 Jun 03.

PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis.

Yaru Xia, Yuqi Han, Weiquan Li, Tiexi Yu, Diaoyi Tan, Daojia Miao, Wen Li, Jiaming Wu, Qianqian Luo, Jiemin Li, Pian Liu, Hongli Liu, Guixiao Huang, Xiaoping Zhang, Hongmei Yang.

Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting. However, the molecular link between tumor metabolic stress and muscle degradation remains elusive. Here, we identify phosphatidylethanolamine-binding protein 4 (PEBP4) as a key regulator of muscle homeostasis under cachectic conditions. PEBP4 expression is markedly suppressed in lung cachectic models and is inversely correlated with tumor-derived lactate levels. Mechanistically, PEBP4 stabilizes NRF2 by competitively binding to KEAP1, enhancing antioxidant defense, inhibiting NF-κB signaling, and downregulating muscle atrophy-related genes MuRF1 and Fbxo32 (also known as Atrogin-1). In vitro and in vivo overexpression of PEBP4 mitigates oxidative stress, preserves muscle mass, and improves strength and endurance in Lewis lung carcinoma tumor-bearing mice. These protective effects are significantly attenuated by NRF2 inhibition, highlighting its critical role in PEBP4-mediated signaling. Collectively, our findings uncover a tumor lactate-PEBP4-NRF2 axis linking cancer metabolism to redox imbalance and muscle wasting, and suggest the therapeutic potential of targeting the PEBP4-NRF2 pathway in lung cancer-associated cachexia.

DOI: https://doi.org/10.1038/s41419-026-08925-5
Cancer Res Commun. 2026 May 20.

Targeting GSTZ1 sensitizes KRAS G12C-mutant lung cancer cells by overcoming glutathione and glycolysis pathway rewiring.

Yi Liao, Xueli Li, Min Liu, Vanessa C Fernandes, Derek Duckett, Eric B Haura, Andrii Monastyrskyi, Uwe Rix.

KRAS mutations are prevalent in lung cancer, but KRAS G12C inhibitors exhibit limited efficacy, partly due to metabolic adaptations, such as enhanced glutathione metabolism and increased glycolysis. Glutathione S-Transferase Zeta 1 (GSTZ1) is a metabolic enzyme that regulates cell metabolism; however, its role in KRAS-driven lung cancer remains underexplored. We recently reported that targeting GSTZ1 significantly enhances the efficacy of FDA-approved KRAS G12C inhibitors in non-small cell lung cancer cells. Untargeted metabolomics now revealed significant alterations in glutathione and glycolytic pathways, marked by lowered lactate levels and increased oxidized glutathione following GSTZ1 ablation. Moreover, pharmacological inhibition of glutathione synthesis and glucose uptake mimicked the sensitizing effects of GSTZ1 targeting. These metabolic shifts were accompanied by increased AMPK phosphorylation and reduced AKT phosphorylation, two key mediators of the response to KRAS G12C inhibition. Our data reveal GSTZ1‑associated metabolic and signaling alterations that contribute to drug resistance and identify GSTZ1 as a potential complementary target to sensitize KRAS mutant NSCLC to KRAS‑directed treatments.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0698
Discov Oncol. 2026 Jun 06.

GFPT2 upregulation predicts poor prognosis and is associated with TGF-β/Smad activation in lung adenocarcinoma.

Zixu Wang, Jiang Fu, Shengjie Tang, Gang Qiu, Shoujun Tang, Tao Liu, Haiyang Hu, Haiyang Guo, Li Yang, Haining Zhou.

   BACKGROUND: Glutamine-fructose-6-phosphate amidotransferase 2 (GFPT2) is a rate-limiting enzyme of the hexosamine biosynthetic pathway, but its protein-level expression and functional relevance in lung adenocarcinoma (LUAD) remain unclear.
METHODS: GFPT2 protein abundance was evaluated in Clinical Proteomic Tumor Analysis Consortium (CPTAC) LUAD proteomics and validated by Western blotting in paired LUAD and adjacent tissues. The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) transcriptomes were analyzed for differential expression and pathway enrichment, with survival assessed by Kaplan-Meier and Cox regression. Stable GFPT2 knockdown/overexpression in A549 cells was used to examine proliferation, migration, invasion, and transforming growth factor-β (TGF-β)/Smad2/3 signaling by Western blotting.
RESULTS: GFPT2 protein was significantly upregulated in LUAD compared with adjacent tissues. TCGA-based analyses showed distinct transcriptional profiles between GFPT2 mRNA-high and GFPT2-low tumors, with enrichment of extracellular matrix organization, cell adhesion, and TGF-β-related signaling. High GFPT2 mRNA expression was associated with poorer overall survival and remained an independent adverse prognostic factor in multivariable Cox models. In A549 cells, GFPT2 overexpression was accompanied by enhanced proliferation, migration, and invasion, whereas GFPT2 knockdown showed the opposite effects. Consistently, GFPT2 upregulation was associated with increased TGF-β1 levels and Smad2/3 phosphorylation, suggesting a positive association with TGF-β/Smad signaling activity.
CONCLUSION: GFPT2 is upregulated at the protein level in LUAD and is associates with aggressive cellular phenotypes and unfavorable prognosis. Integrated multi-omics analyses and cell-based experiments support a link between GFPT2 and TGF-β/Smad2/3 pathway activation, indicating GFPT2 as a potential prognostic biomarker and therapeutic target.

Keywords:  GFPT2; Lung adenocarcinoma; Prognosis; TGF-β signaling

DOI:  https://doi.org/10.1007/s12672-026-05342-0
Cell Death Dis. 2026 Jun 01.

MTHFR functions as a metabolic checkpoint in NSCLC through SLC25A26-mediated SHMT2 inhibition.

Lan Li, YiRan Yang, ShiQing Wang, Dan Li, ChuMao Chen, XinMei Mu, JiaXin Wu, Jin Yuan.

The progression of non-small cell lung cancer (NSCLC) is driven by metabolic plasticity and evasion of apoptotic surveillance, mechanisms that remain incompletely understood. Here, through integrated transcriptomic-metabolomic profiling, molecular interaction mapping, and functional validation, we unveiled a dual regulatory mechanism governed by the MTHFR/SLC25A26 axis that suppresses NSCLC. Clinical cohort analyses revealed concurrent downregulation of MTHFR and SLC25A26 in NSCLC tissues, which strongly correlated with poor prognosis. Mechanistically, MTHFR directly binds and stabilizes SLC25A26, whereas SLC25A26 accelerates SHMT2 degradation via the ubiquitin-proteasome pathway and concurrently suppresses AKT-driven MYB transcriptional activation. This coordinated disruption of serine/one-carbon metabolism and oncogenic signaling significantly inhibited tumor growth in patient-derived xenograft models. Crucially, we identified SLC25A26 as a mitochondrial transporter-ubiquitin adapter hybrid that destabilizes SHMT2 through ubiquitination, whereas its interaction with MTHFR prevents metabolic dysregulation induced by the C677T mutation. Our findings establish the MTHFR/SLC25A26 axis as a master regulator of metabolic-transcriptional crosstalk, providing a therapeutic framework for targeting enzyme stability and kinase signaling in NSCLC treatment.The MTHFR/SLC25A26 axis suppresses NSCLC progression through catalytic activity-dependent stabilization of SLC25A26 by MTHFR, where SLC25A26 functions as a ubiquitin adapter to degrade SHMT2 while concurrently repressing AKT-MYB-driven SHMT2 transcription; clinical downregulation of this axis predicts poor prognosis, and MTHFR overexpression inhibits tumor growth in vivo.

DOI: https://doi.org/10.1038/s41419-026-08874-z
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70318

Novel Long-Acting Ghrelin Analogue PEP-064 Restores Energy Balance in C26 and Lewis Lung Carcinoma-Induced cachexia in Mice.

J E Hunt, C Lund, B Chen, A R Diaz, O Dmytriyeva, J Marcotorchino, K Löbner, K Mörl, N R Andersen, Z K J Ogueboule, E Frank, J Stöhr, D Meseguer, V Panajotova, J Roux, C Clemmensen, L Sylow, M Schneeberger, A G Beck-Sickinger, S L Pedersen, K Fosgerau.

   BACKGROUND: Cancer cachexia is a debilitating syndrome marked by involuntary weight loss resulting from reduced food intake and intricate metabolic reprogramming. Despite its high prevalence, cancer cachexia remains undertreated, with a lack of effective and approved pharmacotherapies. Ghrelin has emerged as a therapeutic target for cancer cachexia due to its beneficial effects on energy balance. However, the clinical application of ghrelin is hampered by its short half-life. In this study, we introduce PEP-064, a novel stabilized, long-acting and efficacious ghrelin analogue and assess its effects on C26-induced and Lewis lung carcinoma (LLC)-induced cachexia in mice.
METHODS: The in vivo efficacy of PEP-064 was evaluated in healthy CD-1 mice after repeated dosing for 7 days and in the C26 and LLC cancer cachexia mouse models. Additionally, the pharmacokinetic profile and whole brain neuronal activity mapping were conducted in healthy mice following a single subcutaneous injection of PEP-064. Growth hormone secretion was measured in healthy rats following a single administration of PEP-064.
RESULTS: In healthy mice, PEP-064 exhibited a dose-dependent (100, 300 and 1000 nmol/kg) increase in both delta body weight (BW) and total food intake (FI) compared to the vehicle (BW: 2.7 g vs. 3.5, 4.8 and 5.3 g; FI: 50 g vs. 57 g, 60 and 70 g). In the C26 model, PEP-064 protected against loss of tumour-free (TF) BW (-1.2 g vs. 1.7 g, p < 0.0001), increased food intake (33 g vs. 41 g, p < 0.01), prevented losses in fat (-1.1 g vs. 0.9 g, p < 0.0001) and lean mass (-0.07 g vs. 0.4 g, p < 0.05) without affecting tumour growth. In the LLC model, PEP-064 induced hyperphagia (52.2 g vs. 61.6 g, p < 0.0001) and protected against TF-BW loss (-1.4 g vs. - 0.01 g, p < 0.05) and fat mass loss (-0.9 g vs. 0.8 g, p < 0.0001). In mice, PEP-064 had a T1/2 of 6.6 h and a Tmax at 4 h. PEP-064 increased neuronal activity (c-Fos) in the hypothalamic and amygdala regions, with the tuberal nucleus of the hypothalamus showing the highest increase compared to the vehicle (p < 0.05). Lastly, circulating growth hormone was increased 20 min after subcutaneous PEP-064 dosing, peaking at 30 min at 93 ng/mL and returning to approximately baseline by 120 min.
CONCLUSIONS: The novel, long-acting and efficacious ghrelin analogue, PEP-064, restored energy balance in cancer cachexia by increasing food intake and body weight, preserving lean mass and increasing adiposity, without affecting tumour growth. Considering the unmet medical need for safe and effective treatments for cachexia, our study demonstrates the feasibility of a long-acting ghrelin approach for treating cancer cachexia.

Keywords:  C26 colon carcinoma; Lewis lung carcinoma; cancer cachexia; ghrelin; peptide

DOI:  https://doi.org/10.1002/jcsm.70318
Cell Mol Biol Lett. 2026 May 31.

Lactate-activated astrocytes promote NSCLC brain metastasis through extracellular vesicle-mediated miR-8085/TRIM67/ELK1 signaling axis.

Haiqin Peng, Guilong Tanzhu, Wen Shi, Gang Xiao, Qian Zeng, Liu Chen, Xin Wan, Di Jing, Haibin Deng, Thomas Michael Marti, Jun Fu, Rongrong Zhou.

  Brain metastasis represents an advanced complication in non-small cell lung cancer (NSCLC), characterized by therapeutic resistance and dismal survival outcomes. Although astrocytes are known to influence tumor progression within the brain microenvironment, their prognostic significance and mechanistic contributions to NSCLC brain metastasis (NSCLC-BM) remain largely unresolved. In this study, we analyze brain metastatic tumors from 66 patients with NSCLC and demonstrate that high infiltration of astrocytes is significantly associated with reduced overall survival. Functional assays reveal that astrocytes enhance the stemness of metastatic tumor cells, a phenotype that is significantly attenuated by silencing astrocytic monocarboxylate transporter 1 (MCT1), thereby blocking lactate uptake. Mechanistically, lactate reprograms astrocytes to release extracellular vesicles enriched in miR-8085, which downregulates the E3 ubiquitin ligase TRIM67 in tumor cells. This suppression stabilizes the transcription factor ELK1 through inhibition of ubiquitin-mediated degradation, promoting stemness maintenance and tumorigenic capacity. Clinically, low TRIM67 and high ELK1 expression correlate with poorer survival in patients with NSCLC-BM. Together, our findings uncover a novel lactate-induced miR-8085/TRIM67/ELK1 signaling cascade that drives brain metastasis progression and highlight potential prognostic biomarkers and therapeutic targets for patients with NSCLC involving the brain.

Keywords:  Astrocyte; Brain metastasis; Extracellular vesicles; Lactate; NSCLC; Tumor stemness

DOI:  https://doi.org/10.1186/s11658-026-00957-1
PLoS One. 2026 ;21(6): e0349820

Exploring hypoxia-related genes as prognostic indicators in lung adenocarcinoma.

Bandar Alghamdi, Sonia Rocha.

BACKGROUND: Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, with hypoxia contributing to tumor progression and treatment resistance. Identifying hypoxia-related biomarkers could enhance prognosis and therapeutic strategies for LUAD.
METHODS: This study aimed to identify hypoxia-related differentially expressed genes (HRDEGs) in lung adenocarcinoma (LUAD) through differential expression analysis. Functional analysis and protein-protein interaction (PPI) network construction were performed to explore the biological roles and interactions of these genes. Kaplan-Meier survival analysis, univariate Cox regression, and Lasso regression were used to identify key genes associated with survival. Multivariate Cox regression was then conducted to assess independent prognostic factors.
RESULTS: This analysis revealed 283 upregulated HRDEGs and 322 downregulated HRDEGs in LUAD. Functional enrichment analysis indicated that the upregulated genes were primarily involved in cancer-related and cellular signaling pathways, while downregulated genes were associated with immunity-related pathways. We further identified 201 common upregulated hub genes (including MMP9, CDH1, HSP90AB1, SOX2, CDKN2A, SPP1, EZH2) and 224 common downregulated hub genes (such as IL6, TNF, IL1B, JUN, CCL2, TLR4, FOS, PTGS2). Kaplan-Meier survival analysis, univariate Cox regression, and Lasso regression led to the identification of 17 key genes (ADRB2, ALDH2, CAT, CCNE1, MAP3K8, DSG2, EIF6, ABCB1, PIK3R1, RAD51, SFTPD, SOD3, CLEC3B, ADAM12, EXO1, FBLN5, and IGF2BP3) associated with patient survival. Finally, multivariate Cox regression analysis identified DSG2, EIF6, and EXO1 as independent prognostic factors for LUAD, highlighting their potential as biomarkers for prognosis and therapeutic targets in lung cancer.
CONCLUSION: In conclusion, DSG2, EIF6, and EXO1 were identified as key hypoxia-related genes in lung adenocarcinoma. These genes were found to be independent prognostic factors, highlighting their potential as biomarkers for predicting patient survival and guiding future therapeutic approaches.

DOI: https://doi.org/10.1371/journal.pone.0349820