bims-meluca 2025-04-06 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–04–06
sixteen papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Increasing cisplatin exposure promotes small-cell lung cancer transformation after a shift from glucose metabolism to fatty acid metabolism.
Peripheral inflammatory factors as prognostic predictors for first-line PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer.
ACAT1 regulates tertiary lymphoid structures and correlates with immunotherapy response in non-small cell lung cancer.
Integrated multi-omics landscape of non-small cell lung cancer with distant metastasis.
Investigation of sphingolipid-related genes in lung adenocarcinoma.
Influence of interleukin-6 on the pharmacokinetics and pharmacodynamics of osimertinib in patients with non-small cell lung cancer.
IDO1-mediated AhR activation up-regulates pentose phosphate pathway via NRF2 to inhibit ferroptosis in lung cancer.
ADH1B regulates tumor stemness by activating the cAMP/PKA/CREB1 signaling axis to inhibit recurrence and metastasis of lung adenocarcinoma.
Fatty acid metabolism-derived prognostic model for lung adenocarcinoma: unraveling the link to survival and immune response.
Hypoxia inducible factor-1α promotes non-small cell lung cancer progression by activating leptin receptor transcription.
A novel lactylation-related gene signature to predict prognosis and treatment response in lung adenocarcinoma.
Taurine and proline promote lung tumour growth by co-regulating Azgp1/mTOR signalling pathway.
The effects of nutritional habits and physical activity on treatment response and survival in patients with lung cancer.
Metabolomic analysis of urethane-induced lung carcinogenesis in rats and the ameliorative effect of Qi-Yu-San-Long decoction.
Lipidomic signatures as predictive biomarkers for early-onset lung cancer: Identification and development of a risk prediction model.
Pathogen adaptation to lung metabolites.

J Cancer Res Clin Oncol. 2025 Mar 28. 151(3): 126

Increasing cisplatin exposure promotes small-cell lung cancer transformation after a shift from glucose metabolism to fatty acid metabolism.

Qiu-Yu Zhao, Wen-Jun Liu, Jian-Guang Wang, He Li, Jia-Lu Lv, Yumeng Wang, Chun Wang.

   OBJECTIVES: Lung cancer is a leading cause of global cancer mortality. Clinical observations reveal that histological transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is accompanied by mutations in TP53 and RB1. By applying gradually increasing cisplatin concentrations to mimic the escalating drug pressure within the tumor microenvironment, this study investigated the link between phenotypic transformation to SCLC in cisplatin-resistant human lung adenocarcinoma cells and alterations in cellular energy production pathways.
MATERIALS AND METHODS: We established two cisplatin-resistant NSCLC cell lines with varying resistance levels. RNAseq analyses identified TP53 and RB1 gene mutations. Comprehensive functional assays were performed to characterize A549/DDP1 μg/mL and A549/DDP3 μg/mL cells, focusing on proliferation and migratory capabilities. Cellular bioenergetics were assessed through glycolysis and oxidative phosphorylation analyses. Western blotting was employed to examine epithelial-mesenchymal transition (EMT), glucose metabolism, and lipid metabolism markers. Cell cycle distribution was analyzed by flow cytometry. Additionally, a xenograft mouse model was developed for in vivo validation.
RESULTS: TP53 and RB1 mutations were associated with cisplatin concentration-dependent phenotypic transformation, with A549/DDP cells acquiring a more aggressive SCLC-like phenotype (In the article we call the A549/DDPSCLC cells). Analysis of cell bioenergetics profiling and Western blot analyses revealed enhanced glucose metabolism in A549/DDP1 μg/mL cells, while A549/DDPSCLC cells exhibited predominant lipid metabolism. Compound3K and Etomoxir specifically inhibit the activity of PKM2 and CPT1A, respectively, with Etomoxir demonstrating substantially inhibited A549/DDPSCLC cells growth and more cell cycle arrest in the G0/G1 phase. Combinatorial of Compound3K and Etomoxir effectively induced cell death in A549/DDPSCLC phenotype cells in vitro. Etomoxir alone or combined with Compound3K significantly inhibited tumor growth in vivo, with enhanced efficacy in the combination group.
CONCLUSIONS: This study provides the first evidence of cisplatin concentration-dependent metabolic reprogramming during NSCLC-to-SCLC transformation. We identified a phenotypic transition from NSCLC to SCLC accompanied by a metabolic shift from glucose to fatty acid metabolism, offering new insights into therapeutic strategies for treatmentresistant lung cancer.

Keywords:   RB1 ; TP53 ; Fatty acid metabolism; Glucose metabolism; NSCLC; Phenotype

DOI:  https://doi.org/10.1007/s00432-025-06164-3
Sci Rep. 2025 Apr 02. 15(1): 11206

Peripheral inflammatory factors as prognostic predictors for first-line PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer.

Chen-Xing Jin, Yan-Song Liu, He-Nan Qin, Yi-Bin Teng, Rui Sun, Zhong-Jing Ma, A-Man Wang, Ji-Wei Liu.

  Immune checkpoint inhibitors (ICIs) have significantly improved the efficacy and prognosis of patients with non-small cell lung cancer (NSCLC). However, there remains a lack of optimal predictive biomarkers for assessing the response of ICIs. This study aimed to evaluate peripheral inflammatory factors as potential predictive biomarkers for NSCLC patients treated with ICIs. We retrospectively analyzed the correlation between peripheral inflammatory factors and the efficacy and prognosis of 124 patients with driver gene-negative advanced NSCLC who received first-line ICIs at our center from September 2018 to June 2022. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. The association between the factors and multiple endpoints were investigated using univariate and multivariate analyses. A total of 124 patients were enrolled in this study. The objective response rate (ORR) was 49.2% and the disease control rate (DCR) was 97.6%, respectively. The median PFS was 12.7 months. The ORR differed statistically between groups based on the NLR, SII, with higher ORR observed in patients with an NLR ratio < 0.68, SII at 6 weeks < 531.26, and SII ratio < 0.74 (p < 0.05). The univariate analysis indicated that ECOG 0-1, smoking, NLR at 6 weeks < 2.72, NLR ratio < 0.68, LMR < 1.34, LMR ratio ≥ 1.38, and SII at 6 weeks < 531.26 were associated with longer PFS (p < 0.05). The multivariate analysis revealed that smoking (p = 0.013), baseline LMR (p = 0.015), and SII at 6 weeks (p = 0.010) were independent predictors of PFS. NLR, LMR, and SII maybe biomarkers for predicting the efficacy and prognosis of first-line ICIs therapy in driver gene-negative advanced NSCLC.

Keywords:  Biomarkers; Immune checkpoint inhibitors; Immunotherapy respond; Neutrophil to lymphocyte ratio; Non-small cell lung cancer; Systemic inflammatory index

DOI:  https://doi.org/10.1038/s41598-024-84469-y
J Clin Invest. 2025 Apr 01. pii: e181517. [Epub ahead of print]135(7):

ACAT1 regulates tertiary lymphoid structures and correlates with immunotherapy response in non-small cell lung cancer.

Mengxia Jiao, Yifan Guo, Hongyu Zhang, Haoyu Wen, Peng Chen, Zhiqiang Wang, Baichao Yu, Kameina Zhuma, Yuchen Zhang, Jingbo Qie, Yun Xing, Pengyuan Zhao, Zihe Pan, Luman Wang, Dan Zhang, Fei Li, Yijiu Ren, Chang Chen, Yiwei Chu, Jie Gu, Ronghua Liu.

  Tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) are emerging solid-tumor indicators of prognosis and response to immunotherapy. Considering that tumorigenesis requires metabolic reprogramming and subsequent TME remodeling, the discovery of TLS metabolic regulators is expected to produce immunotherapeutic targets. To identify such metabolic regulators, we constructed a metabolism-focused sgRNA library and performed an in vivo CRISPR screening in an orthotopic lung tumor mouse model. Combined with The Cancer Genome Atlas database analysis of TLS-related metabolic hub genes, we found that the loss of Acat1 in tumor cells sensitized tumors to anti-PD1 treatment, accompanied by increased TLS in the TME. Mechanistic studies revealed that ACAT1 resulted in mitochondrial protein hypersuccinylation in lung tumor cells and subsequently enhanced mitochondrial oxidative metabolism, which impeded TLS formation. Elimination of ROS by NAC or Acat1 knockdown promoted B cell aggregation and TLS construction. Consistently, data from tissue microassays of 305 patients with lung cancer showed that TLS were more abundant in non-small cell lung cancer (NSCLC) tissues with lower ACAT1 expression. Intratumoral ACAT1 expression was associated with poor immunotherapy outcomes in patients with NSCLC. In conclusion, our results identified ACAT1 as a metabolic regulator of TLS and a promising immunotherapeutic target in NSCLC.

Keywords:  Cancer immunotherapy; Carbohydrate metabolism; Cell stress; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI181517
Front Immunol. 2025 ;16 1560724

Integrated multi-omics landscape of non-small cell lung cancer with distant metastasis.

Teng He, Ting Jiang, Xiaoyuan Sun, Fang Yang, Dan Zhang, Shan Yao, Jiangrong Liao, Xueling Wu.

   Background: Distant metastasis is one of the important factors affecting the prognosis of lung cancer patients. Extracellular vesicles (EVs) play an important role in the occurrence, development, and metastasis of cancer. However, it is currently unclear whether EVs in BALF are involved in distant tumor metastasis.
Methods: we collected bronchoalveolar lavage fluid (BALF) from patients with metastatic and non-metastatic non-small cell lung cancer (NSCLC) to isolate exosomes, which were then characterized by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM), followed by comprehensive metabolomic and proteomic analysis to ultimately construct a distant metastasis prediction model for non-small cell lung cancer.
Results: Our research has found that the BALF of NSCLC patients is rich in EVs, which have typical morphology and size. There are significant differences in protein expression and metabolite types between patients with distant metastasis and those without distant metastasis. Sphingolipid metabolism pathways may be a key factor influencing distant metastasis in NSCLC. Subsequently, we constructed a predictive model for distant metastasis in NSCLC based on differentially expressed proteins identified by proteomics. This model has been proven to have high predictive value.
Conclusion: The multi-omic analysis generated in this study provided a global overview of the molecular changes, which may provide useful insight into the therapy and prognosis of NSCLC metastasis.

Keywords:  exosome; lung cancer; metabolomic; metastasis; proteomics

DOI:  https://doi.org/10.3389/fimmu.2025.1560724
Front Mol Biosci. 2025 ;12 1548655

Investigation of sphingolipid-related genes in lung adenocarcinoma.

Jibin Mao, Li Li, Hui Sun, Jie Han, Jinqiao Li, Chang-Sheng Dong, Hongyu Zhao.

   Background: Lung adenocarcinoma (LUAD) is responsible for majority cases of lung cancer and considered to be the primary cause of cancer-related mortality. The imbalance of cellular proliferation and apoptosis is critically implicated in the pathogenesis and progression of LUAD. Sphingomyelin, a vital lipid component, is integral to the regulation of tumor cell growth and apoptosis, and has garnered significant attention as a target in novel anticancer therapies. The pivotal molecules involved in sphingomyelin metabolism are crucial in modulating tumor cell behavior, thereby influencing clinical outcomes.
Methods: A comprehensive consensus clustering analysis was conducted by collecting clinical LUAD figures from the TCGA and GEO databases. By employing Cox regression and Lasso regression analysis, a prognostic model for LUAD patients was established by identifying seven sphingolipid-related genes (SRGs), and validated in the GEO database. The study also delved into the clinical relevance, functional capabilities, and immune implications of prognostic signals associated with sphingolipid metabolism. Finally, experiments conducted in vitro confirmed the imbalance of sphingolipid-associated genes in LUAD.
Results: Using the prognostic model, lung adenocarcinoma (LUAD) patients can be divided into high-risk and low-risk groups. Meanwhile, we can observe marked disparities in survival times among these groups. Additionally, the model demonstrates high predictive accuracy in external validation cohorts. Research on the immune microenvironment and immunotherapy points to this risk stratification as a useful reference for immunotherapeutic strategies in LUAD. Finally, our hypothesis was corroborated through in vitro experiments.
Conclusion: This study demonstrates that sphingolipid-related gene prognostic characteristics correlate with tumor progression and recurrence, long-term prognosis, and immune infiltration in LUAD patients. The outcomes of our study could help shape innovative strategies for early intervention and prognosis prediction in lung adenocarcinoma.

Keywords:  immune microenvironment; immunohistochemical experiment in vitro; lung adenocarcinoma; prognostic signature; sphingolipid metabolism

DOI:  https://doi.org/10.3389/fmolb.2025.1548655
Cancer Chemother Pharmacol. 2025 Mar 29. 95(1): 49

Influence of interleukin-6 on the pharmacokinetics and pharmacodynamics of osimertinib in patients with non-small cell lung cancer.

Hayato Yokota, Kazuhiro Sato, Sho Sakamoto, Yuji Okuda, Masahide Takeda, Yumiko Akamine, Katsutoshi Nakayama, Masatomo Miura.

   PURPOSE: The inflammatory cytokine interleukin (IL)-6 reduces the activity of drug metabolic enzymes and promotes tumor progression. We investigated the effect of IL-6 on the pharmacokinetics of osimertinib and the association between an IL-6 polymorphism and clinical outcomes in 30 patients with non-small cell lung cancer (NSCLC).
METHODS: Osimertinib and IL-6 plasma concentrations were measured on day 15 after therapy initiation. The genotype of IL-6 1800796G > C was identified using polymerase chain reaction-restriction fragment length polymorphism. Risk factors affecting overall survival (OS) were assessed by Cox proportional hazard regression analysis.
RESULTS: The IL-6 concentration was significantly correlated with the osimertinib trough plasma concentration (r = 0.423, P = 0.020) and area under the plasma concentration-time curve (r = 0.420, P = 0.021). The IL-6 concentration was significantly higher in patients with the IL-6 rs1800796G allele versus C/C genotype (P = 0.024). OS was significantly shorter in patients with the IL-6 rs1800796G allele versus C/C genotype (median: 15.1 vs. 48.9 months, P = 0.005). Univariate and multivariate analyses indicated that the IL-6 rs1800796G allele is an independent risk factor for OS (crude hazard ratio = 7.07; P = 0.014; adjusted hazard ratio = 6.38; P = 0.021).
CONCLUSION: A higher IL-6 concentration was associated with reduced metabolic activity of osimertinib, leading to increased osimertinib exposure. As the IL-6 concentration was higher in NSCLC patients with the IL-6 rs1800796G allele, it might be an independent prognostic factor for patients treated with osimertinib.

Keywords:  Area under the plasma concentration–time curve; Interleukin-6; Osimertinib; Overall survival; Polymorphism; Trough concentration

DOI:  https://doi.org/10.1007/s00280-025-04772-x
Biochem Pharmacol. 2025 Mar 29. pii: S0006-2952(25)00175-3. [Epub ahead of print]236 116913

IDO1-mediated AhR activation up-regulates pentose phosphate pathway via NRF2 to inhibit ferroptosis in lung cancer.

Jiani Zhan, Yijia Chen, Yuying Liu, Yunqiu Chen, Zhiyao Li, Xuewen Li, Zhenning He, Fangzhou Meng, Xiaoyang Qian, Lili Yang, Qing Yang.

  Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.

Keywords:  Ferroptosis; Indoleamine 2,3-dioxygenase 1; Lung cancer; Pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.bcp.2025.116913
Biochem Biophys Res Commun. 2025 Mar 22. pii: S0006-291X(25)00395-X. [Epub ahead of print]760 151681

ADH1B regulates tumor stemness by activating the cAMP/PKA/CREB1 signaling axis to inhibit recurrence and metastasis of lung adenocarcinoma.

Hairong Shi, Youtao Xu, Guoxin Song, Tianzhu Qiu.

  Lung cancer remains the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for approximately 85 % of cases. Despite advancements in diagnostics and therapies, tumor metastasis and drug-resistant recurrence present significant clinical challenges. This study evaluates the prognostic role of ADH1B in lung adenocarcinoma (LUAD) metastasis and recurrence. Analysis of tissue samples from 46 LUAD patients revealed that lower ADH1B expression correlates with increased metastasis and poorer overall survival. Kaplan-Meier survival analysis demonstrated that elevated ADH1B levels are significantly associated with longer overall survival and recurrence-free survival. In vitro experiments indicated that ADH1B overexpression inhibits proliferation, migration, and invasion in A549 and H1299 cell lines. Additionally, ADH1B expression was negatively correlated with tumor stemness markers, indicating its role in suppressing stem cell characteristics. Mechanistically, ADH1B activates the cAMP/PKA/CREB1 signaling pathway, enhancing SOX1 expression and inhibiting the ERK pathway, which contributes to reduced tumor stemness. In vivo studies confirmed that ADH1B overexpression decreases stem cell populations and tumor growth in xenograft models. Our findings suggest that ADH1B functions as a critical regulator of LUAD progression, with its low expression acting as a marker of poor prognosis while promoting metastasis and tumor stemness. This research identifies ADH1B as a potential therapeutic target, offering novel strategies to address the challenges of metastasis and recurrence in LUAD.

Keywords:  LUAD; Metastasis; Tumor stemness; cAMP

DOI:  https://doi.org/10.1016/j.bbrc.2025.151681
Front Immunol. 2025 ;16 1507845

Fatty acid metabolism-derived prognostic model for lung adenocarcinoma: unraveling the link to survival and immune response.

Rui-Ze Wu, Qian-Qian Sun, Yao Fu, Han-Nong Yu, Wei-Yang Liu, Yong-Hui Wu, Han Zhang, Yu-Lin Pan, Xin Rui.

   Background: Lung adenocarcinoma (LUAD) is one of the most common malignant tumors globally, characterized by poor prognosis and high mortality. Abnormal fatty acid metabolism plays a crucial role in LUAD progression. This study aims to develop a prognostic model based on fatty acid metabolism to improve the overall prognosis of LUAD.
Materials and methods: Bioinformatics analyses were performed using TCGA and GEO datasets, supplemented by cell experiments. A total of 309 fatty acid metabolism-related genes were identified from MsigDB. Differentially expressed genes were analyzed using the 'limma' R package. A prognostic model was constructed using LASSO regression and validated with survival analyses via the 'survminer', 'survival', and 'pROC' R packages. The analysis included somatic mutations, tumor mutation burden, clinical correlations, stemness analysis, cytokine correlations, and enrichment analysis. Protein interaction networks were constructed using STRING and Cytoscape, while immune cell infiltration and immunotherapy responses were evaluated with the 'oncoPredict' R package. Results were validated through cell experiments and immunohistochemistry staining of lung tissues.
Results: We identified 125 differentially expressed genes related to fatty acid metabolism, with 33 genes significantly associated with prognosis. Patients in the high-risk group had poorer overall survival and progression-free survival, and the risk score correlated with gender, N stage, clinical stage, and T stage. The risk score was also associated with cancer stem cells, with a significantly higher mRNAsi index in the high-risk group. Additionally, the risk score correlated with various cytokine expressions and showed significant enrichment in cell cycle pathways. Key genes like CDK1 were highly expressed in LUAD cell lines and validated in clinical samples. The low-risk group showed better responses to immune checkpoint inhibitors, with the risk score correlating with immune checkpoint gene expression.
Conclusion: This study successfully established a novel prognostic model based on fatty acid metabolism, which provides valuable insights for the treatment of LUAD.

Keywords:  drug sensitivity analysis; fatty acid metabolism; immune response; lung adenocarcinoma; prognostic model

DOI:  https://doi.org/10.3389/fimmu.2025.1507845
Cancer Biomark. 2025 Feb;42(2): 18758592251330479

Hypoxia inducible factor-1α promotes non-small cell lung cancer progression by activating leptin receptor transcription.

Yan Li, Bo Chen, Shuangshuang Wu, Yijue Zhong, Yuxing Zhang, Jianqing Wu.

  BackgroundHypoxia and leptin receptors (also called obesity receptors, OB-R) are evident markers of tumor progression and have been demonstrated to be essential oncogenes in a variety of cancers. However, the specific role of OB-R in lung cancer, especially non-small cell lung cancer (NSCLC) and its correlation with HIF1α remains unclear. Present study aims to explore the potential functions and mechanisms of OB-R in NSCLC.MethodsThe RNA levels of HIF1α and OB-R in NSCLC cells were detected by quantitative real-time PCR (qRT-PCR) and western blotting. The HIF-1α, OB-R, and Ki67 levels in tumor tissues were detected by immunohistochemistry. CCK8 assays for proliferation, transwell assays for migration were performed to determine the role of HIF-1α and OB-R in vitro, while subcutaneous tumors in nude mice were used for in vivo functional studies. Mechanically, chromatin immunoprecipitation and luciferase reporter gene analyses were executed to determine the relationship between HIF-1α and OB-R.ResultsqRT-PCR and western blotting revealed that HIF-1α and OB-R was highly expressed in NSCLC cells. Moreover, hypoxia up-regulated OB-R expression in NSCLC cells via HIF-1α. Hence, down-regulating HIF-1α significantly reduced the mRNA level of OB-R. In addition, HIF-1α silencing reduced cell proliferation and migration in vitro. Xenograft mouse models indicated that decrease of HIF-1α led to tumor growth by decreasing OB-R in vivo. Mechanically, we unveiled that HIF-1α bound to the promoter region (-831 to -824) and positively regulated OB-R expression by activating its transcription. Additionally, by immunohistochemical staining, we observed that high levels of HIF-1α and OB-R were positively associated with tumor size and lymph node metastasis.ConclusionIn conclusion, our present results demonstrated that HIF-1α positively regulates the expression of OB-R, which acts as an oncogene in NSCLC. HIF-1α and OB-R are potential therapeutic targets in NSCLC.

Keywords:  Hypoxia inducible factor-1α; leptin receptor; non-small cell lung cancer; transcription

DOI:  https://doi.org/10.1177/18758592251330479
Front Oncol. 2025 ;15 1549724

A novel lactylation-related gene signature to predict prognosis and treatment response in lung adenocarcinoma.

Hongyi Zhang, Yihao Liu, Xuanguang Li, Chen Ding, Chunqiu Xia, Hua Huang, Hongyu Liu, Jun Chen.

   Background: Lactylation, a novel post-translational modification, has emerged as a critical regulatory mechanism in various biological processes, including tumor progression. However, its role and associated gene signatures in lung adenocarcinoma (LUAD) remain unclear.
Methods: RNA sequencing data of LUAD patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Unsupervised clustering was used to identify lactylation-related genes. A risk prognostic model was constructed using least absolute shrinkage and selection operator regression analysis and subsequently validated. A nomogram was then employed to optimize the clinical applicability of the risk score. Additionally, various algorithms were used to explore the relationship between the risk score and immune infiltration levels, with model genes analyzed based on single-cell sequencing. The effects of RCCD1 knockdown on LUAD cell proliferation and migration were evaluated through CCK8 and transwell assays.
Results: Higher risk scores were associated with poorer overall survival prognosis. Immune analysis revealed that the risk score may play a role in regulating the tumor microenvironment. Additionally, these risk scores were found to be associated with chemotherapy drug sensitivity. A series of experiments further demonstrated that RCCD1 promotes LUAD cell proliferation and migration in vitro.
Conclusion: This study highlights the critical role of lactylation-related gene signatures in LUAD and their association with immune cell infiltration, providing insights into potential therapeutic targets and biomarkers for clinical application.

Keywords:  bulk RNA sequencing; immune cell infiltration; lactylation-related genes; lung adenocarcinoma; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fonc.2025.1549724
NPJ Precis Oncol. 2025 Mar 28. 9(1): 90

Taurine and proline promote lung tumour growth by co-regulating Azgp1/mTOR signalling pathway.

Tu-Liang Liang, Ying Chen, Nan-Jie Zhou, Xiao Shu, Jia-Ning Mi, Gang-Yuan Ma, Yao Xiao, Xi Yang, Chen Huang, Jia-Xin Li, Ying Xie, Pei-Yu Yan, Xiao-Jun Yao, Liang Liu, Hu-Dan Pan, Elaine Lai-Han Leung, Run-Ze Li.

Accurate metabolic biomarkers for lung cancer prognosis remain scarce but crucial. Taurine and proline, two metabolites, are consistently elevated across various cancer stages in previous studies, hinting at their potential role in disease progression. This study is the first to reveal how these metabolites contribute to poor prognosis. Transcriptomic analysis uncovered that taurine and proline downregulated Zinc-α2-glycoprotein (Azgp1), a gene linked to key metabolic pathways. Additionally, Azgp1 could also significantly affect downstream lipid metabolic pathways in lung cancer. Both taurine and proline influenced lipid metabolism via mammalian target of rapamycin (mTOR). When Azgp1 was overexpressed, lung cancer progression slowed significantly, alongside reduced mTOR activity. These findings underscore the pro-cancer role of taurine and proline, highlighting the Azgp1/mTOR axis as a vital, yet overlooked, pathway in lung cancer. This study not only advances our understanding but also identifies new therapeutic avenues.

DOI: https://doi.org/10.1038/s41698-025-00872-2
Support Care Cancer. 2025 Apr 04. 33(4): 349

The effects of nutritional habits and physical activity on treatment response and survival in patients with lung cancer.

Zeynep Yılmaz Kaya, Deniz Kızılırmak, Yavuz Havlucu.

   BACKGROUND: Lung cancer is a malignancy marked by low treatment response rates and poor survival outcomes, despite significant advancements in diagnostic and therapeutic approaches. This study aims to examine the impact of dietary habits and physical activity levels on chemotherapy response and survival in patients diagnosed with advanced-stage non-small cell lung cancer.
METHODS: Patients diagnosed with stage IV non-small cell lung cancer and scheduled to receive platinum-based chemotherapy as the initial treatment were included in the study. Sociodemographic and cancer-related characteristics were documented. At the beginning of treatment, the patients' dietary habits and physical activity levels were evaluated using the "Mediterranean Diet Adherence Scale," the "International Physical Activity Questionnaire," and the "Food Consumption Frequency Form," while their average daily step count was calculated. The study investigated the relationships between dietary habits and physical activity levels with treatment response, 6-month survival, progression-free survival, and chemotherapy-related side effects.
RESULTS: The study included a total of 37 patients, 35 of whom were male, with a mean age of 63.49 years. The 6-month survival rate among these patients was 81.1%. In terms of treatment response, 35.1% of patients experienced disease progression, 54.1% demonstrated partial regression, and 8.1% achieved complete regression. Notably, the 6-month survival rate was significantly higher in minimally physically active patients compared to inactive patients (p = 0.022). Furthermore, patients adhering to the Mediterranean diet exhibited a significantly higher 6-month survival rate compared to those who did not follow the diet (p = 0.019). High adherence to the Mediterranean diet was also associated with a significantly lower incidence of chemotherapy-related gastrointestinal side effects (p < 0.001).
CONCLUSION: This study demonstrated that physical activity and adherence to the Mediterranean diet positively impact 6-month survival and reduce the incidence of chemotherapy-related side effects.

Keywords:  Lung cancer; Mediterranean diet; Physical activity

DOI:  https://doi.org/10.1007/s00520-025-09409-6
Anal Methods. 2025 Apr 02.

Metabolomic analysis of urethane-induced lung carcinogenesis in rats and the ameliorative effect of Qi-Yu-San-Long decoction.

Lanying Li, Chang Chen, Rui Yang, Ziqi Wei, Ting Zheng, Zegeng Li, Huan Wu.

Lung carcinogenesis (LC) is a kind of disease, which threatens human health seriously. Metabolomic research on bio-fluids and tissues is crucial for elucidating the pathogenesis of LC and understanding the therapeutic mechanisms of medicines. In this study, we established a rat model for LC by induction with urethane. The anti-tumor effect of Qi-Yu-San-Long decoction (QYSLD) on LC was assessed through morphology changes, histopathological examination, and inflammation levels. Utilizing the metabolomics technique based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), we investigated the metabolic changes in the plasma and lungs of LC rats and explored the ameliorative effects of QYSLD on the molecular levels. Functional biomarkers associated with QYSLD in LC rats were identified and relatively quantified. The results manifested that, in contrast to the control group, the number of tumor nodules and inflammation levels in the LC model group increased significantly, indicating that the LC rat model was successfully built. After QYSLD treatment, the morphology and lesion degree of LC rats were greatly improved. A total of 23 differential metabolites between the control group and the urethane-induced LC group were screened through plasma and lung tissue metabolomics studies, of which 20 were considerably modulated after QYSLD treatment. Metabolic pathway analysis revealed that the pathogenesis of LC and the therapeutic effects of QYSLD primarily involved glycerophospholipid metabolism, ether lipid metabolism, sphingolipid metabolism, and arachidonic acid metabolism. Our findings provide a potential intracellular metabolite profile for urethane-induced LC and demonstrate that QYSLD exerts anti-tumor effects on LC by modulating multiple metabolic pathways.

DOI: https://doi.org/10.1039/d4ay02165g
J Adv Res. 2025 Apr 01. pii: S2090-1232(25)00205-X. [Epub ahead of print]

Lipidomic signatures as predictive biomarkers for early-onset lung cancer: Identification and development of a risk prediction model.

Fei Wang, Zeming Guo, Wei Tang, Wei Cao, Xuesi Dong, Yongjie Xu, Chenran Wang, Jiaxin Xie, Xiaoyue Shi, Zilin Luo, Yadi Zheng, Guochao Zhang, Na Ren, Nan Zhang, Donghua Wei, Lingbin Du, Fengwei Tan, Ni Li.

   INTRODUCTION: Lung cancer is the leading cause of cancer-related mortality worldwide. While traditionally associated with older adults, early-onset lung cancer (EOLC) is rising, particularly in Asia, which accounts for 75.9% of global cases. Existing lung cancer screening guidelines primarily focus on older populations, which may result in missed opportunities for early detection in younger individuals. Given its distinct clinical characteristics, EOLC warrants dedicated research and targeted interventions.
OBJECTIVES: This study aims to characterize the lipidomic profiles specific to EOLC patients (aged 18-49 years) and develop a biomarker-based predictive model to improve risk assessment and early detection.
METHODS: The discovery and validation sets included 111 EOLC cases and 127 non-EOLC controls, all aged 18-49 years. Targeted lipidomics analysis, combined with logistic regression, was performed on plasma samples to identify differentially expressed lipids species. Clustering and pathway analyses were conducted to uncover and visualize the internal signatures of the identified lipids. Key lipids were refined using the LASSO-bootstrap regression method combined with the Boruta algorithm. A random forest model was subsequently employed to develop a robust prediction model for EOLC.
RESULTS: A total of 843 lipids were identified, with 60 differentially expressed lipids detected, of which 33 were validated in the validation set. Cluster analysis revealed that passive smoking (OR: 3.11, 95% CI: 0.97-12.11) and current smoking (OR: 15.65, 95% CI: 2.55-142.10) were associated with elevated lipid metabolite profiles in EOLC patients. The validated lipids were further refined using LASSO and Boruta methods, which ultimately selected 6 lipids for inclusion in a prediction model constructed with random forest. This model achieved an area under the curve (AUC) of 0.874 in the validation set.
CONCLUSION: Our study identified lipidomic signatures associated with the risk of EOLC, offering potential translational implications for lung cancer prevention strategies.

Keywords:  Biomarker; Early Onset Lung Cancer; Early detection; Lipidomics; Prediction model

DOI:  https://doi.org/10.1016/j.jare.2025.03.045
Curr Opin Microbiol. 2025 Apr 02. pii: S1369-5274(25)00030-X. [Epub ahead of print]85 102608

Pathogen adaptation to lung metabolites.

Gaurav Kumar Lohia, Sebastián A Riquelme.

Opportunistic pathogens like Pseudomonas aeruginosa and Staphylococcus aureus rapidly adapt to the dynamic metabolic landscape of the respiratory mucosa during infection. Host phagocytes recognize these pathogens and trigger metabolic reprogramming, releasing immunometabolites such as succinate and itaconate. P. aeruginosa preferentially consumes succinate as a carbon source to enhance planktonic growth. In response to itaconate-induced membrane stress, it forms protective biofilms, allowing bacterial survival despite host defenses. Additionally, host ketone bodies support microbial communities that are less immunostimulatory and better tolerated by the lung. Similarly, S. aureus responds to itaconate by forming biofilms, aiding colonization in glucose-limited airways. In this milieu, S. aureus consumes proline, linking its survival with the metabolic activity of proline-producing fibroblasts. Here, we will review the competence of both P. aeruginosa and S. aureus to hijack host metabolic pathways, underscoring pathogen metabolic plasticity as an essential strategy to thrive in the human lung.

DOI: https://doi.org/10.1016/j.mib.2025.102608