bims-meluca 2025-07-13 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–07–13
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Preoperative lipid levels and prognosis in non-small cell lung cancer: A retrospective age-stratified study.
Tumor-secreted RGS17 impairs CD8 + T cell function in lung adenocarcinoma through affecting glucose metabolism mediated by PI3K/AKT pathway.
Lymphopenia, IL6, and CCL2 after thoracic radiotherapy predict poor prognosis in patients with lung cancer.
Resistance training in cachectic pancreatic and lung cancer patients: randomised controlled trial.
NCOA5 suppresses tumor progression and cisplatin resistance in non-small cell lung cancer by interfering with PRDX6 transcription.
Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.
Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.

Sci Prog. 2025 Jul-Sep;108(3):108(3): 368504251352375

Preoperative lipid levels and prognosis in non-small cell lung cancer: A retrospective age-stratified study.

Yv-Xuan Liu, Jing Chen, Chen Liu, Maierhaba Maitiyasen, Xinyv Hou, Jingfeng Li, Jun Yi.

  BackgroundAlthough abnormalities in circulating lipids and lipoproteins are associated with increased cancer risk, their specific impact on lung cancer progression and prognosis is still unclear. This study retrospectively assessed the influence of preoperative lipid and lipoprotein levels on non-small cell lung cancer progression and prognosis, stratified by age.MethodsIn this retrospective study, we analyzed 849 patients to investigate the association between lipid markers and lung cancer progression, and examined postoperative prognosis in a subset of 222 patients. Data was analyzed using restricted cubic spline curves, Kaplan-Meier survival analysis, and Cox proportional hazards models.ResultsA significant nonlinear relationship was observed between total cholesterol (TC), high-density lipoprotein (HDL), ApoB, ApoAI, ApoE, and baseline tumor diameter (BSLD) (PTC = 0.025; PHDL < 0.001; PApoB = 0.037; PApoAI =0.001; PApoE < 0.001). In contrast, Lp(a) showed a significant linear relationship with BSLD (P = 0.002). The Cox regression analysis revealed that triglyceride (TG) (hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.28-0.92, P = 0.025) was significantly negatively associated with lung cancer mortality in patients under 58 years. For patients over 58 years, higher ApoB levels were linked to a reduced risk of lung cancer death (HR = 0.59, 95% CI: 0.36-0.97, P = 0.038).ConclusionThis study reveals a significant negative correlation between ApoAI and HDL levels with BSLD, while Lp(a) shows a positive correlation. In terms of long-term prognosis, high-serum ApoB are associated with a lower mortality risk in all lung cancer patients, and high-serum TG levels associated with reduced mortality risk in patients aged under 58 while high-serum TC levels associated with reduced mortality risk in patients over 58, with high Lp(a) levels indicating a greater risk of mortality in older patients.

Keywords:  NSCLC; baseline tumor diameter; lipids; lung cancer; prognosis

DOI:  https://doi.org/10.1177/00368504251352375
Discov Oncol. 2025 Jul 08. 16(1): 1281

Tumor-secreted RGS17 impairs CD8 + T cell function in lung adenocarcinoma through affecting glucose metabolism mediated by PI3K/AKT pathway.

Ming Lou, Ji-Chun Tong, Qi-Yong Wu, Zheng Zhu, Xiao-Liang Mao, Jia-Wei Lu.

   BACKGROUND: The tumor immune microenvironment (TIME) and its impact on the prognoses and treatment of lung adenocarcinoma (LUAD) represent a major focus of research in this field. The present study primarily elucidates the role of RGS17 in TIME of LUAD.
METHODS: A comprehensive array of analytical methods was employed to assess the gene expression levels, including RT-qPCR, Western blots assay and Immunohistochemistry. The assessment of cell apoptosis and viability was conducted through the utilization of Flow cytometry, Colony formation, or CCK-8 assays. To comprehensively evaluate glycolysis, the glucose consumption, lactate production and extracellular acidification rate (ECAR) were detected.
RESULTS: RGS17 was highly expressed in LUAD patients, which predicted adverse prognosis of LUAD patients. Functionally, RGS17 promoted LUAD tumor growth by hindering the anti-tumor immune response. Specifically, knockdown of RGS17 in tumor cells was observed to result in increased CD8 + T cell infiltration into the tumors, thereby impeding LUAD tumor growth. Furthermore, tumor-secreted RGS17 impeded CD8 + T cell function by reducing IFN-γ and Granzyme B secretion, thus impeding the anti-tumor immune response. Mechanically, RGS17 impeded glycolysis in CD8 + T cells by regulating the PI3K/AKT pathway.
CONCLUSION: Tumor-secreted RGS17 impairs CD8 + T cell cytotoxicity in LUAD through impeding glycolysis mediated by PI3K/AKT pathway, thereby promoting tumor growth.

Keywords:  CD8 + T cell; Glucose metabolic reprogramming; Lung adenocarcinoma; PI3K/AKT pathway; RGS17

DOI:  https://doi.org/10.1007/s12672-025-02850-3
J Formos Med Assoc. 2025 Jul 08. pii: S0929-6646(25)00343-2. [Epub ahead of print]

Lymphopenia, IL6, and CCL2 after thoracic radiotherapy predict poor prognosis in patients with lung cancer.

Jenny Ling-Yu Chen, Yu-Sen Huang, Yong-Han Su, Ching-Ying Kuo, Yeun-Chung Chang.

   BACKGROUND/PURPOSE: This study evaluated the impact of lymphopenia and serum biomarkers, including interleukin-6 (IL-6) and chemokine (C-C motif) ligand 2 (CCL2), on survival in patients with NSCLC treated with curative-intent thoracic radiotherapy.
METHODS: Seventy-five patients with NSCLC treated with curative-intent thoracic radiotherapy were included. Baseline and post-radiotherapy lymphocyte counts, serum IL-6, and CCL2 levels were assessed. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were analyzed.
RESULTS: At baseline, patients with NSCLC exhibited significantly elevated serum IL-6 and CCL2 levels compared to those of healthy controls (p < 0.05). Thoracic radiotherapy significantly decreased lymphocyte counts (p < 0.001). Severe lymphopenia and elevated post-treatment IL-6 and CCL2 levels correlated with shorter OS and PFS (p < 0.05). Patients with the three prognostic factors-severe lymphopenia and elevated post-treatment IL-6 and CCL2 levels-exhibited the poorest outcomes, with an estimated mean PFS of 13.5 months and OS of 29.7 months. Notably, these biomarkers demonstrated greater prognostic value in the advanced-stage subgroup. Moreover, bioinformatics analysis revealed that elevated CCL2 expression was associated with poorer clinical outcomes, an immunogenic tumor microenvironment, and upregulation of immune-related pathways, making it a potential biomarker for prognosis and treatment.
CONCLUSION: Post-treatment lymphopenia and elevated serum IL-6 and CCL2 are significant prognostic markers in patients with NSCLC undergoing thoracic radiotherapy. Immunologic evaluation may guide adjuvant treatment strategies in NSCLC treated with radiotherapy.

Keywords:  CCL2; Interleukin-6; Lung cancer; Lymphopenia; Survival outcomes

DOI:  https://doi.org/10.1016/j.jfma.2025.07.007
BMJ Support Palliat Care. 2025 Jul 08. pii: spcare-2025-005516. [Epub ahead of print]

Resistance training in cachectic pancreatic and lung cancer patients: randomised controlled trial.

Timo Niels, Lisa Stich, Stefanie Siebert, Sarah Man, Nico DeLazzari, Mitra Tewes, Helen Schörghofer, Dirk Waldschmidt, Freerk T Baumann.

   OBJECTIVES: Pancreatic and lung cancer are associated with cancer cachexia (CC), which negatively impacts patients' quality of life, treatment outcomes and prognosis. This study aimed to evaluate the feasibility and effectiveness of a 24-week eccentrically overloaded resistance training (ERT) in patients with CC.
METHODS: 22 patients with pancreatic or lung cancer and CC were randomised (2:1) to either supervised ERT (n=14) and usual care (UC, n=8). ERT was performed twice weekly for 24 weeks. Feasibility was assessed through recruitment rate, dropouts, adverse events (AEs) and exercise adherence. Secondary outcomes included body composition, physical performance and patient-reported outcomes (PROs) in quality of life, fatigue, anxiety and depression, anorexia-cachexia symptoms and physical activity levels. Assessments were conducted at baseline, 12 weeks (ITT1) and after 24 weeks (ITT2).
RESULTS: The recruitment rate was 21.8%. 10 dropouts (45.5%) were recorded (ERT: n=7, UC n=3). Clinical AEs were comparable between the groups. Two AEs occurred during or after an exercise session, but resolved completely. The exercise adherence was 63.7%. After 12 weeks, the ERT group improved significantly in aerobic capacity, functional strength and several PROs, while the UC group improved in PROs depression and physical activity levels. After 24 weeks, body composition worsened in the UC group compared with the ERT group (p=0.026). Intragroup analysis showed improvements in PRO domains in the ERT group and decreases of the phase angle in the UC group.
CONCLUSIONS: Supervised ERT seems feasible in cachectic cancer patients and may preserve or enhance physical performance, constitution and PROs.

Keywords:  Cachexia; Cancer; Pancreatic; Rehabilitation; Supportive care

DOI:  https://doi.org/10.1136/spcare-2025-005516
Biochem Pharmacol. 2025 Jul 05. pii: S0006-2952(25)00367-3. [Epub ahead of print]240 117102

NCOA5 suppresses tumor progression and cisplatin resistance in non-small cell lung cancer by interfering with PRDX6 transcription.

Dan-Ni Wu, Ping Huang, Kang-Liang Zhang, Rui-Heng Chen, Ri-Sheng Huang.

  Cisplatin (CDDP)-based chemotherapy is an important treatment modality for non-small cell lung cancer (NSCLC), yet its efficacy is limited by the development of drug resistance. Chemoresistance is associated with aberrant lipid metabolism. We analyzed differentially expressed lipid metabolism-related genes based on public data and searched for a novel regulator of NSCLC chemoresistance. NCOA5, a regulator of cholesterol efflux, was found to be downregulated in CDDP-resistant NSCLC cells and surgically resected NSCLC tissues. Low NCOA5 expression was significantly associated with lymph node metastasis, TNM stage, and prognosis in NSCLC. NCOA5 knockdown increased the proliferation, invasion, and tumorigenesis of NSCLC cells. Overexpression of NCOA5 reversed the CDDP resistance of NSCLC cells both in vitro and in vivo. The chemosensitive effect of NCOA5 on CDDP-resistant NSCLC cells was impaired by N-acetylcysteine, an inhibitor of reactive oxygen species (ROS). Mechanistic investigations revealed that NCOA5 repressed PRDX6 expression by interfering with NRF2-mediated transactivation. Depletion of PRDX6 phenocopied the NCOA5-overexpressing cells and resulted in increased ROS generation and CDDP sensitivity. Furthermore, enforced expression of PRDX6 blunted the effects of NCOA5 on ROS production and CDDP sensitivity in NSCLC cells. Our data reveal a crucial role for NCOA5 in NSCLC progression and CDDP resistance. Thus, targeting the NCOA5/PRDX6 axis may be a promising strategy to overcome CDDP resistance in NSCLC.

Keywords:  Chemotherapy; Lung cancer; NCOA5; Oxidative stress

DOI:  https://doi.org/10.1016/j.bcp.2025.117102
Sci Rep. 2025 Jul 09. 15(1): 24651

Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.

Jiang He, Tangmin Lai, Zhiying Zhou, Haonan Yang, Zheng Lei, Liu Zhou, Nan Li, Yu He, Siwei Zeng, Erha Munai, Yuanyuan Tan, Miaomiao Wang, Yang Zhang, Wei Zhou, Yongzhong Wu.

The novel protein acylation modifications have played a vital role in protein post-translational modifications. However, the functions and effects of the protein acylation modifications in lung adenocarcinoma are still uncertain. Currently, there is still a lack of global identification of acylation modifications in lung adenocarcinoma cells. Therefore, in this study, we detected 10 currently known acylation modifications in lung adenocarcinoma cells by Western blot. We found that the abundance of lysine lactylation (Kla), crotonylation (Kcr) and succinylation (Ksu) is likely higher. Subsequently, we identified the above three modifications together with phosphorylation by global mass spectrometry-based proteomics in lung adenocarcinoma cells. As a result, we got 3110 Kla sites in 1220 lactylated proteins, 16,653 Kcr sites in 4137 crotonylated proteins, 4475 Ksu sites in 1221 succinylated proteins, and 15,254 phosphorylation sites in 4139 phosphorylated proteins. Recent studies have highlighted the role of lactylation modifications in tumor cell resistance to radiation and chemotherapy by affecting homologous recombination. Our subsequent investigations have shown that key factors in the nonhomologous end joining (NHEJ) pathway, such as Ku70 and Ku80, undergo lactylation modifications. Inhibition of lactylation impairs the efficiency of nonhomologous end joining. In conclusion, our results provide a proteome-wide database to study Kla, Kcr and Ksu and phosphorylation in lung adenocarcinoma, and new insights into the role of acylation modification in lung adenocarcinoma.

DOI: https://doi.org/10.1038/s41598-025-09937-5
Adv Sci (Weinh). 2025 Jul 10. e13084

Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.

Yun Xu, Shumin Li, Jiaji Wu, Shumin Xu, Mo Shen, Chenyang Wang, Lundqvist Andreas, Jianghao Yu, Zhiyong Xu, Yueli Shi, Nana Liu, Yunke Yang, Jiangnan Zhao, Ying Yang, Pingli Wang, Peng Yi, Jin Cheng, Junhui Sun, Mengshu Li, Peng Xiao, Kai Wang.

  Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has shown promising therapeutic effects in the treatment of lung cancer, the overall efficacy of PD-1/PD-L1 inhibitors is only 20%-30%. Thus, more effective combination therapies are needed. This study finds that cystine and cysteine levels in tumor tissues of lung cancer patients are significantly higher than adjacent non-tumor tissues. Cystine deficiency polarizes macrophages toward an M1 phenotype, secreting more TNF-α, CXCL9, and CXCL10. However, using a cystine-free diet marginally reduces the development of lung cancer in vivo. A cystine-free diet slightly reduces lung cancer progression in vivo. Further studies show that cystine deprivation or erastin-mediated transport inhibition increased PD-L1 expression in macrophages both in vitro and in vivo. Combining a cystine-free diet or IKE injection with PD-L1 antibody treatment significantly inhibited subcutaneous tumor growth in mice. Mechanistic studies indicat that cystine deficiency-induced GSH depletion activates NF-κB in macrophages by reducing its glutathionylation. This effect can be reversed by replenishing GSH or using an NF-κB inhibitor. At the same time, lung cancer patients with better responses to immunotherapy are found to have lower serum GSH levels. These findings suggest that targeting cystine metabolism combined with PD-L1 inhibition is a promising therapeutic strategy.

Keywords:  PD‐L1; cystine; immunotherapy; lung cancer; macrophage polarization; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202413084