bims-meluca 2025-03-23 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–03–23
thirteen papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Obesity promotes immunotherapy efficacy by up-regulating the glycolytic-mediated histone lactacylation modification of CD8+ T cells.
Correlation between cancer cachexia and psychosocial impact in older patients with advanced lung cancer undergoing chemotherapy.
Prognostic Value of 18F-FDG PET/CT Metabolic Parameters in Resectable Non-small Cell Lung Cancer Treated With Neoadjuvant Immunotherapy Plus Chemotherapy.
Specific effects of hypoxia-immune core gene ARHGAP11A on lung adenocarcinoma.
CircRUNX1 enhances the Warburg effect and immune evasion in non-small cell lung cancer through the miR-145/HK2 pathway.
Novel selective strategies targeting the BCL-2 family to enhance clinical efficacy in ALK-rearranged non-small cell lung cancer.
Aspirin impedes non-small cell lung cancer development via fine-tuning the CD36 localization regulated by GPIHBP1.
Identifying Lipid Metabolism-Related Therapeutic Targets and Diagnostic Markers for Lung Adenocarcinoma by Mendelian Randomization and Machine Learning Analysis.
A novel pathway for stemness propagation and chemoresistance in non-small cell lung cancer via phosphorylated PKM2-loaded small extracellular vesicles.
Nutritional Approach on Management of Diarrhea Induced by EGFR-TKI's in Advanced Non-Small Cell Lung Cancer Patients.
NNMT promotes acquired EGFR-TKI resistance by forming EGR1 and lactate-mediated double positive feedback loops in non-small cell lung cancer.
A Novel Definition and Grading Diagnostic Criteria for Tumour-Type-Specific Comprehensive Cachexia Risk.
Metabolic pathway activation and immune microenvironment features in non-small cell lung cancer: insights from single-cell transcriptomics.

Front Pharmacol. 2025 ;16 1533464

Obesity promotes immunotherapy efficacy by up-regulating the glycolytic-mediated histone lactacylation modification of CD8+ T cells.

Kai-Xuan Wang, Dong-Min Shi, Xiao-Li Shi, Jing-Yuan Wang, Xing-Hao Ai.

  The response rate of immune checkpoint blockade (ICB) therapy for non-small-cell lung cancer (NSCLC) remains limited. Recent evidence suggests that obese cancer patients are more likely to benefit from ICB therapy, however, the specific mechanism needs further research. In this study, we found that anti-PD-1 therapy was more effective in obese NSCLC patients compared to normal weight patients and this was verified in mouse NSCLC model. Further bioinformatics analysis indicated that the glycolytic metabolism was markedly elevated in obese NSCLC patients. In vitro co-culture experiment showed that both increased glycolysis of tumor cells and external addition of lactate promoted T cell PD-1 expression. And, PD-1 upregulation was related to monocarboxylate transporter 1 (MCT1)-mediated lactate transport and subsequent lysine lactylation of histones in T cells. Based on the aforementioned data, our study contributes to better application of anti-PD-1 therapy in NSCLC.

Keywords:  MCT1; NSCLC; PD-1; histone lactacylation; immunotherapy

DOI:  https://doi.org/10.3389/fphar.2025.1533464
Asia Pac J Oncol Nurs. 2025 Dec;12 100658

Correlation between cancer cachexia and psychosocial impact in older patients with advanced lung cancer undergoing chemotherapy.

Rika Sato, Tateaki Naito, Haruyasu Murakami, Shota Omori, Haruki Kobayashi, Akira Ono, Nobuaki Mamesaya, Kazushige Wakuda, Ryo Ko, Hirotsugu Kenmotsu, Sakiko Aso, Miho Hasaba, Keita Mori, Toshiaki Takahashi, Naoko Hayashi.

   Objective: This study aimed to evaluate the association of cancer cachexia with psychosocial impact, nutrition impact symptoms (NIS), and geriatric assessment in older patients newly diagnosed with advanced lung cancer undergoing chemotherapy.
Methods: Older patients with advanced lung cancer scheduled to receive first-line chemotherapy between August 2021 and February 2022 were enrolled. Cachexia was diagnosed according to the International Consensus. NIS and psychosocial impacts were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ) C30, CAX24, and the Eating-Related Distress Questionnaire (ERD). Non-parametric tests evaluated the association between cachexia and its impacts. Patients with cachexia who consented to be interviewed were asked about their experiences with diet and weight changes. Three authors reviewed the interview data to ensure the analysis's veracity.
Results: Twenty-one of the 31 participants (68%) had cachexia at baseline. The cachexia group showed significantly greater severity of Food Aversion (P = 0.035), Eating and Weight Loss Worry (P < 0.001), and Loss of Control (P = 0.005) compared to the non-cachexia group. There were no significant differences in the ERD and geriatric assessment (all P > 0.05). The interview revealed that patients with cachexia perceived diet and weight changes early on and tried to manage their symptoms by themselves.
Conclusions: Cancer cachexia showed an association with NIS and psychosocial impacts. Older patients with advanced lung cancer scheduled to receive first-line chemotherapy should undergo a comprehensive assessment of cancer cachexia, including its potential physical and psychological impacts.
Trial registration: The trial registration number was UMIN 000053843.

Keywords:  Cancer cachexia; Eating-related distress; Geriatric assessments; Nutrition impact symptoms; Oncology nursing; Prospective longitudinal study

DOI:  https://doi.org/10.1016/j.apjon.2025.100658
Clin Nucl Med. 2025 Mar 20.

Prognostic Value of 18F-FDG PET/CT Metabolic Parameters in Resectable Non-small Cell Lung Cancer Treated With Neoadjuvant Immunotherapy Plus Chemotherapy.

You Cheng, Zhen-Peng Jiang, Xiao-Bo Chen, Kai-Yu Lu, Zai-Yi Liu, Dan Shao.

OBJECTIVE: This study investigates the predictive value of 18F-FDG PET/CT metabolic parameters in patients with non-small cell lung cancer (NSCLC) undergoing neoadjuvant immunotherapy plus chemotherapy.
METHODS: We conducted a retrospective analysis of clinical data from 131 patients with pathologically confirmed NSCLC who were deemed resectable after 3 cycles of neoadjuvant immunotherapy plus chemotherapy. Pretreatment and post-treatment PET metabolic parameters were evaluated. CT assessments based on immune response evaluation criteria in solid tumors (iRECIST) were compared with PET/CT assessments using the response criteria in solid tumors (PERCIST). ROC curve analysis and Kaplan-Meier survival analysis, including univariate and Cox multivariate analyses, were employed to assess the prognostic value of PET metabolic parameters after treatment.
RESULTS: The PET/CT assessment based on PERCIST showed high consistency with prognosis, while the CT assessment based on iRECIST demonstrated low consistency. Statistically significant differences were observed between the iRECIST and PERCIST criteria (P<0.001). ROC curve analysis revealed significant differences in post-treatment PET metabolic parameters (postSUVmax, postSUVmean, postSUVpeak, postMTV, and postTLG) as well as the percentage changes in metabolic parameters before and after treatment(Δ) (ΔSUVmax, ΔSUVmean, ΔSUVpeak, ΔMTV, and ΔTLG) (P<0.05). Optimal cutoff values enabled stratification into high-risk and low-risk groups. Univariate analysis showed significantly higher survival in the low-risk group for all parameters except ΔMTV (P=0.311), while Cox multivariate analysis identified ΔSUVmax as the most predictive.
CONCLUSIONS: The PERCIST is more accurate than iRECIST in evaluating prognosis for NSCLC neoadjuvant immunotherapy plus chemotherapy. PET metabolic parameters, particularly ΔSUVmax, effectively predict prognosis and support clinical decision-making.

DOI: https://doi.org/10.1097/RLU.0000000000005863
Transl Cancer Res. 2025 Feb 28. 14(2): 778-795

Specific effects of hypoxia-immune core gene ARHGAP11A on lung adenocarcinoma.

Kang Sun, Luyao Wang, Xueying Zhang, Huili Chen, Ziqiang Wang, Jing Zhang, Xiaojing Wang, Chaoqun Lian.

   Background: The changes in tumor microenvironment (TME) are closely related to the regulation of immunity and hypoxia. This study aimed to investigate the specific effects of ARHGAP11A on the prognosis, immunity, and hypoxia of lung adenocarcinoma (LUAD).
Methods: The core gene ARHGAP11A related to immunity and hypoxia was obtained from a variety of databases, including Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), the Search Tool for the Retrieval of Interacting Genes (STRING), HALLMARK gene set, and various analysis methods (differences and single factor Cox analysis). The relationship between the expression level of ARHGAP11A, survival prognosis, immune invasion, and hypoxia regulation was analyzed.
Results: ARHGAP11A was associated with poor patient prognosis and was strongly associated with immune and hypoxic-related signal pathways. We also found that knocking down the expression of ARHGAP11A can affect the proliferation, glycolysis, migration, invasion, and anti-apoptotic ability of tumor cells. The changes of apoptosis-related proteins (BCL2, BAX, and Caspase-3), cell cycle protein E1, D1 (cyclin D1, cyclin E1), matrix metalloproteinase 2 and 9 (MMP2, MMP9), and P-Phosphatidylinositol 3-kinase and protein kinase B (P-PI3K and P-AKT) in the knockdown group, were verified by Western blot (WB). We also found that interfering with the expression of ARHGAP11A can reduce the expression of programmed cell death ligand 1 (PDL1) in LUAD cells. Through the induction of tumor cells by cobalt chloride (CoCL2), we established a hypoxic microenvironment, and found that interfering with ARHGAP11A can significantly reduce the expression of hypoxia-inducible factor 1A (HIF1A), downstream molecular vascular endothelial growth factor A (VEGFA), and lactate dehydrogenase A (LDHA).
Conclusions: The expression of ARHGAP11A is highly correlated with immunity, hypoxia, poor prognosis, and tumor cell development. Therefore, the study of ARHGAP11A can provide more ideas on comprehensive treatment and prognosis management of LUAD.

Keywords:  ARHGAP11A; Lung adenocarcinoma (LUAD); hypoxia; immune microenvironment; prognosis

DOI:  https://doi.org/10.21037/tcr-24-224
Cancer Lett. 2025 Mar 14. pii: S0304-3835(25)00203-4. [Epub ahead of print] 217639

CircRUNX1 enhances the Warburg effect and immune evasion in non-small cell lung cancer through the miR-145/HK2 pathway.

Jinyou Li, Shiwei Xu, Yangyang Zhan, Xinyi Lv, Zhenyu Sun, Li Man, Donghua Yang, Yahong Sun, Shengguang Ding.

  Non-small cell lung cancer (NSCLC) is acknowledged as the primary subtype of lung cancer. The Warburg effect, marked by elevated glucose consumption and lactate fermentation, is a prevalent characteristic of NSCLC. The mechanisms by which circRNA mediates the regulation of the Warburg effect and immune evasion in NSCLC remain unclear.. This study found an elevated circRNA, circRUNX1, whiche promotes glycolysis and lactate generation, resulting in the infiltration of regulatory T cell (Treg) in NSCLC. circRUNX1 acts as a miR-145 sponge, inhibiting its negative regulation of the target gene HK2, therefore facilitating glycolysis and lactate generation. The accumulation of lactic acid in the tumor microenvironment promotes Treg cell proliferation and aids immune evasion. Functionally, the suppression of circRUNX1 significantly impedes tumor development both in vitro and in vivo. These findings collectively clarity a previously unexamined mechanism linking the circRUNX1/miR-145/HK2 axis in regulation of the Warburg effect and immune evasion in NSCLC.

Keywords:  Immune evasion; NSCLC; Treg cell; Warburg effect; circRUNX1

DOI:  https://doi.org/10.1016/j.canlet.2025.217639
Cell Death Dis. 2025 Mar 20. 16(1): 194

Novel selective strategies targeting the BCL-2 family to enhance clinical efficacy in ALK-rearranged non-small cell lung cancer.

Fernando Martín, Clara Alcon, Elba Marín, Paula Morales-Sánchez, Albert Manzano-Muñoz, Sherley Díaz, Mireia García, Josep Samitier, Albert Lu, Alberto Villanueva, Noemí Reguart, Cristina Teixido, Joan Montero.

ALK (anaplastic lymphoma kinase) rearrangements represent the third most predominant driver oncogene in non-small cell lung cancer (NSCLC). Although ALK inhibitors are the tyrosine kinase inhibitors (TKIs) with the longest survival rates in lung cancer, the complex systemic clinical evaluation and the apoptotic cell death evasion of drug-tolerant persister (DTP) cancer cells may limit their therapeutic response. We found that dynamic BH3 profiling (DBP) presents an excellent predictive capacity to ALK-TKIs, that would facilitate their use in a clinical setting and complementing the readout of standard diagnostic assays. In addition, we revealed novel acute adaptive mechanisms in response to ALK inhibitors in cell lines and patient-derived tumor cells. Consistently, all our cell models confirmed a rapid downregulation of the sensitizer protein NOXA, leading to dependence on the anti-apoptotic protein MCL-1 after treatment with ALK-TKIs. In some cases, the anti-apoptotic protein BCL-xL may contribute equally to this anti-apoptotic response. Importantly, these acute dependencies could be prevented with BH3 mimetics in vitro and in vivo, blocking tumor adaptation to treatment. Finally, we also demonstrated how dual reactivation of PI3K/AKT and MAPK signaling pathways can impair lorlatinib response, which could be overcome with specific inhibitors of both signaling pathways. In conclusion, our findings propose several therapeutic combinations that should be explored in future clinical trials to enhance ALK inhibitors efficacy and improve the clinical response in a broad NSCLC patient population.

DOI: https://doi.org/10.1038/s41419-025-07513-3
Transl Lung Cancer Res. 2025 Feb 28. 14(2): 491-512

Aspirin impedes non-small cell lung cancer development via fine-tuning the CD36 localization regulated by GPIHBP1.

Wei Liu, Dujuan Qiao, Jia Chen, Ya Gao, Katsuhiro Okuda, Yoshihisa Shimada, Linong Yao.

   Background: Lung cancer, a commonly diagnosed malignancy, is the leading cause of cancer-related death worldwide. Aspirin suppresses the progression and metastasis of various cancers. However, the effect of aspirin on non-small cell lung cancer (NSCLC) has not been fully understood. It has been established that glycosylphosphatidylinositol HDL-binding protein 1 (GPIHBP1) and CD36 play a vital role in lipid metabolism and transport. This study aimed to clarify the mechanism by which aspirin inhibits NSCLC cell proliferation and metastasis via GPIHBP1.
Methods: The blood and tissues of 10 patients with NSCLC treated with aspirin and 10 patients without aspirin were collected and analyzed via RNA sequencing. GPIHBP1 expression was determined by immunohistochemistry (IHC), Western blotting, and quantitative real time polymerase chain reaction (qRT-PCR). A series of functional experiments were performed to evaluate the effects of aspirin on NSCLC progression in a GPIHBP1-dependent manner. The potential mechanism of GPIHBP1 was explored via coimmunoprecipitation and immunofluorescence staining. The effect of GPIHBP1 on tumor growth and metastasis was verified by constructing subcutaneous xenograft tumor model in nude mice.
Results: GPIHBP1 was downregulated and was increased by treatment with aspirin in lung cancer tissues. Furthermore, GPIHBP1 overexpression inhibited the migration, cell proliferation, and epithelial-mesenchymal transition process in NSCLC cells while promoting their apoptosis, while in cells with GPIHBP1 knockdown, the opposite was observed. Mechanistically, GPIHBP1 directly interacted with CD36 while GPIHBP1 knockdown disrupted CD36 localization, thus promoting tumor progression and metastasis in NSCLC cells. In addition, through in vivo xenograft experiments, we found that GPIHBP1 overexpression inhibited tumor growth and metastasis.
Conclusions: Our findings provide new insights into the mechanism by which aspirin suppresses lung cancer development in a GPIHBP1-dependent manner and may provide a promising target in NSCLC treatment.

Keywords:  Aspirin; glycosylphosphatidylinositol HDL-binding protein 1 (GPIHBP1); metastasis; non-small cell lung cancer (NSCLC); proliferation

DOI:  https://doi.org/10.21037/tlcr-2024-1174
Thorac Cancer. 2025 Mar;16(6): e70020

Identifying Lipid Metabolism-Related Therapeutic Targets and Diagnostic Markers for Lung Adenocarcinoma by Mendelian Randomization and Machine Learning Analysis.

Su Wei, Zhou Guangyao, Tian Xiangdong, Guo Feng, Zhang Lianmin, Zhang Zhenfa.

   BACKGROUND: Lipid metabolic disorders are emerging as a recognized influencing factors of lung adenocarcinoma (LUAD). This study aims to investigate the influence of lipid metabolism-related genes (LMRGs) on the diagnosis and treatment of LUAD and to identify significant biomarkers.
METHODS: DESeq2 and robust rank aggregation (RRA) analyses were employed to determine the differential expression of LMRGs from TCGA-LUAD and five GEO datasets. Mendelian randomization (MR) was conducted utilizing protein quantitative trait loci (pQTLs) in the deCODE, prot-a, and UKB-PPP Study to estimate causal relationships between plasma proteins and LUAD within the ieu-a-984, ieu-a-965, and FinnGen R10 cohorts as potential drug targets of LUAD. Subsequently, an optimal machine learning model for diagnosing LUAD was established by comparing four models: support vector machine, random forest (RF), glmBoost, and eXtreme Gradient Boosting. Finally, the diagnostic performance of five plasma proteins was validated through nomogram analysis, calibration curve assessment, decision curve analysis (DCA), independent internal and external datasets.
RESULT: A total of five biomarkers were identified from 1034 LMRGs via MR and differential expression analysis. TNFRSF21 exhibited a positive association with LUAD risk; conversely, BCHE, FABP4, LPL, and PLBD1 demonstrated negative correlations with this risk. The RF machine learning model was determined to be the optimal model for diagnosing LUAD using these five plasma proteins. Ultimately, nomogram construction, calibration curve analysis, DCA, as well as independent internal and external dataset validation confirmed that these biomarkers exhibit excellent diagnostic performance.
CONCLUSIONS: BCHE, FABP4, LPL, PLBD1, and TNFRSF21 represent potential novel reliable diagnostic markers as well as therapeutic targets for LUAD.

Keywords:  Mendelian randomization; lipid metabolism; lung adenocarcinoma; machine learning

DOI:  https://doi.org/10.1111/1759-7714.70020
Theranostics. 2025 ;15(8): 3439-3461

A novel pathway for stemness propagation and chemoresistance in non-small cell lung cancer via phosphorylated PKM2-loaded small extracellular vesicles.

Jingyi Wang, Liu Liu, Xinyu Gao, Xiyu Liu, Yitian Dai, Zijun Mao, Shengzhe Huang, Junjian Li, Dongliang Wang, Yu Qi, Yingwen Han, Yunjing Xu, Corrine Ying Xuan Chua, Alessandro Grattoni, Wenhui Xie, Hao Yang, Gang Huang.

  Rationale: Non-small cell lung cancer (NSCLC) is a predominant cause of cancer-related mortality, with its progression and treatment resistance significantly influenced by cancer stem cells (CSCs) and their complex intercellular communication mechanisms. Small extracellular vesicles (sEVs) have emerged as pivotal mediators of intercellular signaling, affecting tumor microenvironment modulation and therapeutic resistance. This study investigates the role of CSC-derived sEVs in transmitting stemness traits through the selective sorting of pyruvate kinase M2 phosphorylated at the Y105 site (pY105-PKM2), mediated by the adaptor protein IQGAP1, which supports CSC maintenance and drug resistance in NSCLC. Methods: In vitro and in vivo experiments, including proteomic and transcriptomic analyses, were conducted to identify key regulators of sEV-mediated signaling. Immunoprecipitation, proximity ligation assays, and immunofluorescence were used to examine the role of IQGAP1 in the sorting of pY105-PKM2 into sEVs. Functional assays, including sphere formation, chemoresistance tests, metabolic assessments, and cell cycle analysis, were conducted to evaluate the effects of sEV-mediated delivery of pY105-PKM2 on recipient cells. Additionally, immunohistochemistry and survival analysis were performed on tumor samples from NSCLC patients to establish clinical correlations. Results: We unveiled a novel mechanism by which CSC-derived sEVs transmit stemness traits to replenish the CSC pool in NSCLC. CSC-derived sEVs were enriched with pY105-PKM2, correlating with enhanced stemness, chemoresistance, and poor clinical outcomes. Mechanistically, IQGAP1 was identified as an adaptor facilitating the selective sorting of pY105-PKM2 into sEVs through interactions with the ESCRT component TSG101. Recipient cells treated with CSC-derived sEVs exhibited metabolic reprogramming, slower cell cycle progression, and enhanced chemoresistance. The synergistic role of IQGAP1 and pY105-PKM2 was confirmed, highlighting their critical contributions to CSC maintenance and malignant progression. Conclusion: This study highlights the critical role of CSC-derived sEVs in NSCLC progression and therapy resistance through the IQGAP1-mediated selective sorting of pY105-PKM2. By uncovering this novel pathway, our findings provide valuable insights into CSC pool replenishment and therapeutic resistance mechanisms in NSCLC, identifying IQGAP1 and pY105-PKM2 as promising therapeutic targets for mitigating CSC-driven malignancy and enhancing treatment efficacy.

Keywords:  IQGAP1; cancer stem cells; drug resistance; pY105-PKM2; small extracellular vesicles

DOI:  https://doi.org/10.7150/thno.103722
Nutr Cancer. 2025 Mar 19. 1-8

Nutritional Approach on Management of Diarrhea Induced by EGFR-TKI's in Advanced Non-Small Cell Lung Cancer Patients.

Jenny G Turcott, Daniela Cárdenas-Fernández, Karla Sánchez-Lara, Cittim B Palomares-Palomares, Oscar Arrieta.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Adenocarcinoma is the most prevalent subtype of Non-Small Cell Lung Cancer (NSCLC), and platinum-based chemotherapy is the standard first-line treatment. However, patients harboring EGFR mutations benefit significantly from tyrosine kinase inhibitor (TKI) therapy, which enhances treatment response, prolongs progression-free survival (PFS), and improves overall survival (OS). Despite these advantages, TKI-associated gastrointestinal toxicity, particularly mucositis and diarrhea, poses a major challenge that often affects treatment adherence and patient quality of life. Effective diarrhea management is crucial for maintaining therapeutic continuity, yet current clinical guidelines primarily focus on pharmacological approaches. This review highlights the critical role of nutritional strategies in preventing and mitigating TKI-induced diarrhea. Due to the irritative effects of TKIs on digestion, dietary modifications are crucial. Patients should avoid greasy, spicy, acidic, and high-fiber foods, along with alcohol, soft drinks, and coffee. Steamed, baked, or boiled foods are recommended. Glutamine and probiotics may aid mucosal recovery and microbiota balance. Ongoing nutritional oversight and individualized dietary guidance are essential for patients with NSCLC undergoing TKI therapy. Future research should establish evidence-based dietary guidelines to optimize treatment tolerance, enhance patient well-being, and improve clinical outcomes.

DOI: https://doi.org/10.1080/01635581.2025.2478649
Mol Cancer. 2025 Mar 15. 24(1): 79

NNMT promotes acquired EGFR-TKI resistance by forming EGR1 and lactate-mediated double positive feedback loops in non-small cell lung cancer.

Jiali Dai, Xiyi Lu, Chang Zhang, Tianyu Qu, Wei Li, Jun Su, Renhua Guo, Dandan Yin, Pingping Wu, Liang Han, Erbao Zhang.

   BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, patients inevitably develop acquired drug resistance, resulting in recurrence or metastasis. It is important to identify novel effective therapeutic targets to reverse acquired TKI resistance.
RESULTS: Bioinformatics analysis revealed that nicotinamide N-methyltransferase (NNMT) was upregulated in EGFR-TKI resistant cells and tissues via EGR1-mediated transcriptional activation. High NNMT levels were correlated with poor prognosis in EGFR-mutated NSCLC patients, which could promote resistance to EGFR-TKIs in vitro and in vivo. Mechanistically, NNMT catalyzed the conversion of nicotinamide to 1-methyl nicotinamide by depleting S-adenosyl methionine (the methyl group donor), leading to a reduction in H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) and subsequent epigenetic activation of EGR1 and ALDH3A1. In addition, ALDH3A1 activation increased lactic acid levels, which further promoted NNMT expression via p300-mediated histone H3K18 lactylation on its promoter. Thus, NNMT mediates the formation of a double positive feedback loop via EGR1 and lactate, EGR1/NNMT/EGR1 and NNMT/ALDH3A1/lactate/NNMT. Moreover, the combination of a small-molecule inhibitor for NNMT (NNMTi) and osimertinib exhibited promising potential for the treatment of TKI resistance in an NSCLC osimertinib-resistant xenograft model.
CONCLUSIONS: The combined contribution of these two positive feedback loops promotes EGFR-TKI resistance in NSCLC. Our findings provide new insight into the role of histone methylation and histone lactylation in TKI resistance. The pivotal NNMT-mediated positive feedback loop may serve as a powerful therapeutic target for overcoming EGFR-TKI resistance in NSCLC.

Keywords:  EGFR-TKI resistance; Histone lactylation; Histone methylation; Lung cancer

DOI:  https://doi.org/10.1186/s12943-025-02285-y
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13744

A Novel Definition and Grading Diagnostic Criteria for Tumour-Type-Specific Comprehensive Cachexia Risk.

Chunlei Hu, Minghua Cong, Chunhua Song, Hongxia Xu, Zengqing Guo, Fuxiang Zhou, Lan Zhou, Min Weng, Benqiang Rao, Li Deng, Kaiying Yu, Yongbing Chen, Ziwen Wang, Guotian Ruan, Ming Yang, Chenan Liu, Jiuwei Cui, Wei Li, Kunhua Wang, Zengning Li, Ming Liu, Tao Li, Junqiang Chen, Stephan von Haehling, Rocco Barazzoni, Hanping Shi.

   BACKGROUND: The existing diagnostic criteria for cancer cachexia do not meet clinical needs. We aimed to establish novel comprehensive evaluation scales for cachexia specific to patients with solid tumours.
METHODS: This study included 12 651 patients (males: 6793 [53.7%]; females: 5858 [46.3%]; medium age: 58 [interquartile range:50/66] years; medium follow-up duration: 24.16 [13.32/44.84] months; 4271 [33.8%] patients died; mean survival: 55.53 [95% confidence interval, 54.87/56.10] months; 3344 [26.4%], 4184 [33.1%] and 5123 [40.5%] patients with Stage I-II, III and IV tumour, respectively; derivation set: 10022, validation set: 2629 patients) with 14 types of solid tumours, including lung, gastric, liver, breast, oesophageal, cervical, bladder, pancreatic, prostate, ovarian, colorectal cancer, nasopharyngeal and endometrial carcinoma and cholangiocarcinoma, from an open and ongoing multicentre cohort study in China. Risk factors for cachexia, including tumour characteristics and nutritional parameters, were examined to develop diagnostic scales using Cox proportional hazards models and Kaplan-Meier analysis.
RESULTS: Ten nutrition items (body mass index, weight loss, intake reduction, physical activity function, fatigue, handgrip strength, anorexia, albumin level, albumin/globulin ratio and neutrophil/lymphocyte ratio) with different weighted scores were identified to construct a nutrition-weighted scoring scale (NWSS) for nutrition risk. Tumour type and tumour burden status (tumour-node-metastasis stage and radical or non-radical tumour) were determined to construct a disease-weighted scoring scale (DWSS) for disease risk. A lumped scale (5 × 5 matrix) established using a five-grade classification of nutrition and disease risk was used to determine a five-grade classification of comprehensive cachexia risk: A, no cachexia risk (reference; lowest disease and nutrition risks); B, cachexia risk (hazard ratio [HR] = 4.517 [4.033/5.058]); C, pre-cachexia (HR = 9.755 [8.73/10.901], medium survival = 21.21 months); D, cachexia (HR = 16.901 [14.995/19.049], medium survival = 11.61 months); and E, refractory cachexia (HR = 31.879 [28.244/35.981], medium survival = 4.83 months, highest disease and nutrition risks) (p < 0.001). Patients in Categories A-D benefited from nutrition therapy and anti-tumour treatments to varying degrees. Patients in Category E were clinically refractory to nutrition therapy without prolonged survival compared with patients without nutrition therapy (medium survival, pre-hospitalization nutrition therapy vs. hospitalization nutrition therapy vs. without nutrition therapy, 2.89 [1.91/3.88] vs. 4.04 [3.21/4.88] vs. 5.89 [4.73/7.04] months, p = 0.015) and anti-tumour treatments without prolonged survival compared with patients receiving palliative care (medium survival, radical anti-tumour treatments vs. adjuvant anti-tumour treatments vs. palliative anti-tumour treatments vs. and palliative care, 6.48 [4.42/8.53] vs. 6.48 [3.23/9.73] vs. 4.83 [4.22/5.44] vs. 2.70 [1.09/4.30] months, p = 0.263).
CONCLUSION: We systematically developed a novel definition and grading diagnostic criteria for tumour-type-specific comprehensive cancer cachexia risk.

Keywords:  cancer cachexia; comprehensive cancer cachexia risk; diagnostic criteria; solid tumour; tumour‐type‐specific diagnosis

DOI:  https://doi.org/10.1002/jcsm.13744
Front Immunol. 2025 ;16 1546764

Metabolic pathway activation and immune microenvironment features in non-small cell lung cancer: insights from single-cell transcriptomics.

Yanru Liu, Hanmin Liu, Ying Xiong.

   Introduction: In this study, we aim to provide a deep understanding of the tumor microenvironment (TME) and its metabolic characteristics in non-small cell lung cancer (NSCLC) through single-cell RNA sequencing (scRNAseq) data obtained from public databases. Given that lung cancer is a leading cause of cancer-related deaths globally and NSCLC accounts for the majority of lung cancer cases, understanding the relationship between TME and metabolic pathways in NSCLC is crucial for developing new treatment strategies.
Methods: Finally, machine learning algorithms were employed to construct a risk signature with strong predictive power across multiple independent cohorts. After quality control, 29,053 cells were retained, and PCA along with UMAP techniques were used to distinguish 13 primary cell subpopulations. Four highly activated metabolic pathways were identified within malignant cell subpopulations, which were further divided into seven distinct subgroups showing significant differences in differentiation potential and metabolic activity. WGCNA was utilized to identify gene modules and hub genes closely associated with these four metabolic pathways.
Results: Our analysis showed that DEGs between tumor and normal tissues were predominantly enriched in immune response and cell adhesion pathways. The comprehensive examination of our model revealed substantial variations in clinical and pathological characteristics, enriched pathways, cancer hallmarks, and immune infiltration scores between high-risk and low-risk groups. Wet lab experiments validated the role of KRT6B in NSCLC, demonstrating that KRT6B expression is elevated and it stimulates the proliferation of cancer cells.
Discussion: These observations not only enhance our understanding of metabolic reprogramming and its biological functions in NSCLC but also provide new perspectives for early detection, prognostic evaluation, and targeted therapy. However, future research should further explore the specific mechanisms of these metabolic pathways and their application potentials in clinical practice.

Keywords:  metabolic pathway; non-small cell lung cancer; risk signature; tumor microenvironment; weighted gene co-expression network analysis

DOI:  https://doi.org/10.3389/fimmu.2025.1546764