bims-meluca 2025-09-07 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–09–07
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.
Multi-omic profiling of squamous cell lung cancer identifies metabolites and related genes associated with squamous cell carcinoma.
Cross-species analysis identifies genotype-driven vulnerabilities in lung adenocarcinoma.
Nutrition in lung cancer treatment: the forgotten pillar of care?
Identification and validation of PSMB7 as a novel biomarker for prognosis and immune infiltrates of lung adenocarcinoma.
Involvement of Perk and ATF6 Signal Pathways in Indicating Unfolded Protein Response in Patients with Chronic Lymphocytic Leukaemia.
Targeting DDX3X suppresses progression of KRAS-driven lung cancer by disrupting antioxidative homeostasis and inducing ferroptosis.

Mol Biol Rep. 2025 Sep 03. 52(1): 861

The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.

Yan Zhang, Ying Wu, Aoxing Cheng, Fengjuan Cui, Zhenye Yang, Jing Guo.

   BACKGROUND: Malignant tumors are characterized by their reliance on hyperactive glycolysis (Warburg effect), marked by increased glucose uptake, lactate secretion, and preferential glucose flux into glycolysis and the pentose phosphate pathway (PPP). These metabolic shifts provide energy, biosynthetic precursors, and maintain redox balance, supporting tumor proliferation. However, the regulatory crosstalk between glycolysis and PPP remains poorly understood. This study investigates how tumors coordinate these pathways to drive progression via metabolic reprogramming.
METHODS AND RESULTS: Exogenous lactate supplementation in A549 cells increased the NADPH/NADP+ ratio, enhanced fatty acid synthesis, and upregulated the PPP. Western blotting revealed lactylation of glucose-6-phosphate dehydrogenase (G6PD), which correlated with intracellular lactate levels, modulated by rotenone treatment or lactate dehydrogenase A (LDHA) overexpression. LDHA knockdown significantly reduced G6PD lactylation. Enzyme assays confirmed that lactylation enhanced G6PD activity. Through truncation and mutagenesis analyses, we identified lysines 45-47 as the key lactylation site, which enhances NADP⁺ binding and promotes G6PD dimerization. Mutation of this site impaired cancer cell proliferation and migration in vitro and suppressed tumor growth in vivo. Mechanistically, G6PD lactylation serves as a metabolic switch, linking PPP activation to oncogenic progression.
CONCLUSIONS: Lactate drives tumor progression through G6PD lactylation, activating the PPP and facilitating glycolysis-PPP crosstalk. This study uncovers a novel metabolic rewiring mechanism that promotes oncogenic synergy.

Keywords:  Cancer; Glucose-6-phosphate dehydrogenase; Lactylation; Pentose phosphate pathway

DOI:  https://doi.org/10.1007/s11033-025-10960-y
Mol Oncol. 2025 Sep 03.

Multi-omic profiling of squamous cell lung cancer identifies metabolites and related genes associated with squamous cell carcinoma.

Johan Staaf, Daniel Ehinger, Hans Brunnström, Mats Jönsson, Frida Rosengren, Marija Kotevska, Anna Karlsson, Mattias Aine, Christian Frezza, Maria Planck, Elsa Arbajian.

  Squamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant cell metabolism is a hallmark of carcinogenesis. This study aimed to identify SqCC-specific key regulators that could eventually be used as new anticancer targets. Transcriptional and metabolomic data were gathered for a cohort of resected lung cancers. SqCC-specific differentially expressed genes were integrated with metabolic data. Findings were validated in cohorts of tumors, normal specimens, and cell lines. In situ protein expression of SLC6A8 was investigated. Differential gene expression analysis identified a subset of SqCC-specific genes with metabolic functions through the Reactome database, and/or correlated to specific metabolites through GEMs models. Metabolic profiling identified seven SqCC-specific metabolites, of which increased creatine levels, in particular, matched to SqCC-specific expression of SLC6A8. Expression of the gene appeared tumor cell-associated. Elevated creatine levels and overexpression of its transporter SLC6A8 appear a distinct metabolic feature of SqCC. Considering ongoing clinical trials in other malignancies, exploring SLC6A8 inhibition in SqCC appears motivated based on a metabolic addiction hypothesis.

Keywords:  SLC6A8; creatine; lung cancer; metabolomics; squamous cell lung carcinoma

DOI:  https://doi.org/10.1002/1878-0261.70121
bioRxiv. 2025 Aug 27. pii: 2025.08.24.671070. [Epub ahead of print]

Cross-species analysis identifies genotype-driven vulnerabilities in lung adenocarcinoma.

Angeliki Karatza, Maayan Pour, Jaylen M Powell, Yuan Hao, Dimitris Nasias, Yi Jer Tan, Alfonso Lopez, Metamia Ciampricotti, Chengwei Peng, Alvaro Quintanal Villalonga, Yeuan Ting Lee, Ruveyda Ayasun, Muhammad Elnaggar, Priyanka Sahu, Igor Dolgalev, Hai Hu, Luis Chiriboga, Cynthia Loomis, Daniel Andrussier, Magdalena Ploszaj, Aristotelis Tsirigos, Peter Meyn, Fred P Davis, Nicolas Stransky, Gromoslaw A Smolen, John Thomas Poirier, Jonathan So, Mark Philips, Harvey Pass, Dafna Bar Sagi, Itai Yanai, Kwok-Kin Wong.

While three major genetic alteration subsets, characterized by mutations in STK11, KRAS , and EGFR , are seminal in driving tumorigenesis in LUAD, their distinct effects on tumor cells and the tumor microenvironment are not fully understood. Here, we map critical oncogenic subset-specific vulnerabilities by identifying conserved cell-type-specific reprogrammings between human and mouse LUAD. Through harmonized scRNA-seq analysis of 57 human and 18 mouse specimens, we unveil that genetic alterations impose genotype-specific immune imprints on the tumor microenvironment: KRAS is associated with a transitional immune state, whereas STK11 and EGFR mutations define discrete and contrasting immune phenotypes. We find that STK11-mutant tumors exhibit complement and interferon-rich immune microenvironments while EGFR-mutant tumors harbor a naive T cell-rich phenotype accompanied by a global HLA downregulation, stress-responsive alveolar macrophages marked by MARCO. In the epithelial compartments, cross-species analysis reveals metabolic dependencies, including OGDH in EGFR- and PDE4D in STK11-mutant cells.
Statement of Significance: This study delineates oncogenotype-specific molecular and immune imprints in lung adenocarcinoma, revealing STK11-, KRAS-, and EGFR-mutated tumors as transcriptionally and immunologically discrete ecosystems. By mapping epithelial vulnerabilities alongside immune imprints, we unveil genotype-imposed dependencies that inform the rational development of precision therapies with direct translational relevance.

DOI: https://doi.org/10.1101/2025.08.24.671070
Chin Clin Oncol. 2025 Aug;14(4): 43

Nutrition in lung cancer treatment: the forgotten pillar of care?

José Pablo Miramontes-González, Álvaro Rodrigo-Alaíz, Laisa Briongos-Figuero, Alejandro Olivares-Hernández, Juana Carretero-Gómez, Miriam Gabella-Martín, Julia Sebastián-Rodríguez, Luis Corral-Gudino.

  Malnutrition and cachexia in cancer patients, particularly those with lung cancer, represent a pervasive clinical challenge that compromises treatment outcomes, quality of life, and overall survival. This article analyzes the multifactorial etiology of oncological malnutrition, highlighting the chronic inflammatory state, tumor-induced anorexia, and metabolic abnormalities that accelerate muscle and weight loss. It underscores that rates of malnutrition can range from 30% to 80% across different tumor types, with lung cancer patients especially vulnerable due to their high inflammatory burden. The text reviews key tools for screening and diagnosing malnutrition, such as Nutriscore, Subjective Global Assessment (SGA), and Patient-Generated Subjective Global Assessment (PG-SGA), as well as the relevance of the Glasgow Prognostic Score in linking inflammation with poorer clinical outcomes. Strategies for early nutritional intervention include enteral and parenteral feeding, oral nutritional supplements (ONS), and customized dietary counseling. Additionally, specialized approaches such as immunonutrition, omega-3 fatty acids, and targeted micronutrient supplementation are discussed, reflecting evidence that multiple nutrients, including arginine and glutamine, can exert immunomodulatory and anti-inflammatory effects. Furthermore, the article emphasizes the importance of identifying and managing cancer-associated sarcopenia, in which screening tools like Strength, Assistance with walking, Rise from chair, Climb stairs, Falls (SARC-F)/calf circumference (CalF) offer early detection of muscle mass deficits. Psychological support and patient education are positioned as integral components of a holistic intervention plan, aimed at optimizing nutritional status and mitigating the side effects of chemotherapy and radiotherapy. Ultimately, the need for larger-scale randomized clinical trials is highlighted to refine best practices, establish standardized methodologies, and confirm the clinical benefits of comprehensive nutritional therapies in patients with lung cancer.

Keywords:  Cancer; lung cancer; nutrition; sarcopenia

DOI:  https://doi.org/10.21037/cco-25-42
PeerJ. 2025 ;13 e19958

Identification and validation of PSMB7 as a novel biomarker for prognosis and immune infiltrates of lung adenocarcinoma.

Yan Chen, Xin Ran, Ping Fu, Jie Ao, Guihua Zhu, Lianhua Zhao, HuaLiang Xiao.

   Background: Lung adenocarcinoma (LUAD) is one of the most prevalent types of lung cancer globally; it is characterized by high incidence and mortality rates and contributes to over 1.8 million deaths annually. PSMB7, a crucial component of the 20S proteasome involved in protein degradation and antigen presentation, has been implicated in various cancers; however, its specific function in LUAD remains inadequately explored.
Methods: This research aimed to investigate the expression of PSMB7 in LUAD and its clinical significance using real-time quantitative PCR, immunohistochemistry, differential expression analysis, pathway enrichment analysis, immune cell infiltration, and DNA methylation.
Results: PSMB7 expression levels in LUAD tissues were considerably higher than those in the surrounding normal lung tissues and were associated with advanced pathological stages and poorer clinical outcomes. High PSMB7 expression was correlated with reduced overall and disease-specific survival. Functional enrichment analysis indicated that the differentially expressed genes associated with PSMB7 were mainly involved in protein-DNA complex assembly and chromatin remodeling. Moreover, LUAD tissues showed lower DNA methylation in PSMB7 promoters than that in normal lung tissues, which was correlated with reduced survival rates. A negative correlation was observed between PSMB7 levels and immune cell infiltration, particularly for effector memory T, B, follicular helper T, and mast cells.
Conclusions: We identified PSMB7 as a promising biomarker for LUAD prognosis because of its strong association with tumor progression and immune microenvironment modulation. Future studies should explore therapeutic strategies targeting PSMB7 to improve patient outcomes for LUAD.

Keywords:  Biomarker; Immune microenvironment; Lung adenocarcinoma; PSMB7; Prognosis

DOI:  https://doi.org/10.7717/peerj.19958
Biomarkers. 2025 Aug 29. 1-12

Involvement of Perk and ATF6 Signal Pathways in Indicating Unfolded Protein Response in Patients with Chronic Lymphocytic Leukaemia.

Nergiz Erkut, Merve Kestane, Selim Demir, Ahmet Mentese, Ozlen Balta, Mehmet Sonmez.

   INTRODUCTION: PERK, ATF6, and IRE1α signalling pathways are unfolded protein response (UPR) signalling pathways. In this study, we evaluated the effect of PERK and ATF6 signalling pathways, which are UPR signalling pathways, in chronic lymphocytic leukaemia (CLL) patients.
METHODS: ELISA was performed on peripheral blood plasma samples from CLL patients and the control group for the markers eIF2AK3, GRP78, ATF6, CHOP, HIF-1α and caspase 3.
RESULTS: In this study, the levels of eIF2AK3, GRP78, ATF6 and CHOP were higher in the CLL group than in the control group (p = <0.001, p = <0.001, p = <0.001, p = <0.001, respectively). While no difference was observed between the CLL group and the control group in terms of HIF-1α level, caspase 3 level was higher in the CLL group (p = <0.001). There was a positive relationship between the level of HIF-1α and the levels of ATF6 and CHOP (r = 0.648, p = <0.001; r = 0.727, p = <0.001, respectively). Also, a positive correlation was observed between caspase 3 level and ATF6 level (r = 0.301, p = 0.030).
DISCUSSION: In this study, markers associated with PERK and ATF6 signalling pathways were higher in CLL patients.

Keywords:  ATF6 signaling pathway; Endoplasmic reticulum stress; PERK signaling pathway; apoptosis; hypoxia

DOI:  https://doi.org/10.1080/1354750X.2025.2553628
Cell Death Dis. 2025 Aug 30. 16(1): 660

Targeting DDX3X suppresses progression of KRAS-driven lung cancer by disrupting antioxidative homeostasis and inducing ferroptosis.

Meijuan Dian, Liang Yun, Qingyu Meng, Songwen Lin, Ming Ji, Ying Zhou, Wenqian Liu, Zhuoying Yang, Yayan Zhao, Gaoyuan Li, Jianjun Jiang, Weichao Hao, Zhijie Chen, Zehao Zhou, Ruihao Zhang, Tianyuan Liu, Yujing He, Tianbao Yan, Haofei Wang, Shane J F Cronin, Josef M Penninger, Kaican Cai, Shuan Rao.

Approximately 30% of human cancers carry various RAS mutations, including KRAS, NRAS, and HRAS. Among these mutations, KRAS is the most prevalent isoform detected in lung cancer. While several small molecular inhibitors targeting specifically KRASG12C have been developed and tested clinically, alternative approaches are still necessary due to expected drug resistance. In this study, we present evidence that the loss of DDX3X significantly delays tumor progression in various KRAS-driven lung cancer models. Inhibition of DDX3X disrupts cysteine and glutathione metabolism, thereby inducing ferroptosis in lung cancer cells. This effect is primarily mediated by the downregulation of Cystathionine-β-synthase (CBS), the rate-limiting enzyme in cysteine generation. Mechanistically, DDX3X directly binds to the transcription factor JUND, which mediates the transcriptional regulation of METTL16, a key N6-methyladenosine methyltransferase, and subsequently regulates m6A modification and translation of CBS transcripts. This cascade induces hypermethylation and high expression of CBS, consequently triggering cysteine production and maintaining antioxidative homeostasis, which is essential for the survival of KRAS-driven lung cancer cells. Finally, we demonstrate that a newly developed DDX3X PROTAC degrader J10 efficiently delays lung cancer progression with multiple advantages compared to DDX3X small molecular inhibitor RK-33 and limited side effects. These findings unveil the potential of DDX3X as a valuable target for adjuvant therapies in managing KRAS-driven lung cancer.

DOI: https://doi.org/10.1038/s41419-025-07980-8