bims-meluca 2025-11-09 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–11–09
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.
Targeting FSP1 triggers ferroptosis in lung cancer.
Effect of preoperative cancer cachexia on postoperative sarcopenia in patients with non-small cell lung cancer.
Tumoral ALOX5 mediated arachidonic acid metabolism regulates immune response in non-small cell lung cancer.
PHF10 is a Novel Substrate of Keap1 to Protect Non-Small-Cell Lung Cancer (NSCLC) Cells Against Oxidative Stress and Confer Ferroptosis Resistance.
The role of tyrosine metabolism-associated genes in predicting lung adenocarcinoma prognosis and their clinical relevance.
Proteome-wide Mendelian randomization and colocalization analysis uncovers druggable targets for lung cancer across multiple phenotypes and complications.

Cell Stem Cell. 2025 Nov 03. pii: S1934-5909(25)00373-X. [Epub ahead of print]

Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.

Jin Young Lee, Nabora Reyes, Sang-Ho Woo, Nancy C Allen, Tsukasa Kadota, Andrew Lechner, Ritusree Biswas, Sakshi Goel, Fia Stratton, Chaoyuan Kuang, Tatsuya Tsukui, Vincent Auyeung, Aaron S Mansfield, Lindsay M LaFave, Tien Peng.

  Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16Ink4a+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16Ink4a+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identifies XL888, an HSP90 inhibitor, that clears p16Ink4a+ cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

Keywords:  cancer-associated fibroblasts; lung adenocarcinoma; p16(INK4a); senescence; senolytics; spatial transcriptomics; tumor cell plasticity; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.stem.2025.10.005
Nature. 2025 Nov 05.

Targeting FSP1 triggers ferroptosis in lung cancer.

Katherine Wu, Alec J Vaughan, Jozef P Bossowski, Yuan Hao, Aikaterini Ziogou, Seon Min Kim, Tae Ha Kim, Mari N Nakamura, Ray Pillai, Mariana Mancini, Sahith Rajalingam, Mingqi Han, Toshitaka Nakamura, Lidong Wang, Suckwoo Chung, Diane Simeone, David Shackelford, Yun Pyo Kang, Marcus Conrad, Thales Papagiannakopoulos.

Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation1-3. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and can be leveraged therapeutically remains unknown4,5. Here, using genetically engineered mouse models of lung adenocarcinoma, we performed tumour-specific loss-of-function studies of two key ferroptosis suppressors, GPX46,7 and ferroptosis suppressor protein 1 (FSP1)8,9, and observed increased lipid peroxidation and robust suppression of tumorigenesis, suggesting that lung tumours are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions. Lipidomic analyses revealed that Fsp1-knockout tumours had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary or pharmacological approaches effectively restored the growth of Fsp1-knockout tumours in vivo. Unlike GPX4, expression of FSP1 (also known as AIFM2) was prognostic for disease progression and poorer survival in patients with lung adenocarcinoma, highlighting its potential as a viable therapeutic target. To this end, we demonstrated that pharmacologic inhibition of FSP1 had significant therapeutic benefit in pre-clinical lung cancer models. Our studies highlight the importance of ferroptosis suppression in vivo and pave the way for FSP1 inhibition as a therapeutic strategy for patients with lung cancer.

DOI: https://doi.org/10.1038/s41586-025-09710-8
Support Care Cancer. 2025 Nov 07. 33(12): 1027

Effect of preoperative cancer cachexia on postoperative sarcopenia in patients with non-small cell lung cancer.

Kengo Shirado, Shota Okuno, Kenta Kawamitsu, Takashi Kido, Takako Eto, Manabu Yasuda, Toshihiro Yamashita.

   OBJECTIVE: Many patients with lung cancer have cancer cachexia, which may result in complications and affect prognosis; however, its preoperative prevalence is unknown. Skeletal muscle mass loss after lung cancer surgery also affects prognosis. Although cachexia and sarcopenia share some similarities, whether preoperative cachexia affects postoperative sarcopenia is still unknown. Thus, we designed a cohort study of patients with non-small cell lung cancer (NSCLC) to investigate this.
RESEARCH METHODS AND PROCEDURES: Patients with NSCLC who underwent surgery and perioperative rehabilitation were included in this study. The prevalence of preoperative cachexia and the association between preoperative cachexia and sarcopenia 1 month after surgery were tested using propensity-score matching. After matching, the regression analysis was performed to investigate whether preoperative cachexia was independently related to sarcopenia 1 month postoperatively.
RESULTS: In total, 126 patients (73 men) median age 71 (interquartile range 67, 76) years were included in the study. Preoperative cachexia was present in 16 (12.7%) patients, and postoperative sarcopenia was present in 29 (23%) patients. Among the 126 patients, 16 and 32 patients were included in the preoperative cachexia and control groups, respectively, as a result of matching (standardized mean difference < 0.1). After matching, regression analysis showed that preoperative cachexia was independently associated with sarcopenia at 1 month postoperatively (odds ratio 4.33, p = 0.020).
CONCLUSIONS: Among the patients with NSCLC, 12.7% had preoperative cachexia. Preoperative cachexia in patients with NSCLC affected sarcopenia 1 month postoperatively.

Keywords:  Cachexia; Non-small cell lung cancer; Rehabilitation; Sarcopenia; Surgery

DOI:  https://doi.org/10.1007/s00520-025-10089-5
Cell Oncol (Dordr). 2025 Nov 05.

Tumoral ALOX5 mediated arachidonic acid metabolism regulates immune response in non-small cell lung cancer.

Yuan Gao, Yangchen Xia, Jiayao Li, Yongfeng Lai, Songlin Yin, Junhong Lin, Dongrunhan Yu, Shanshan Huang, Fujia Lu, Weimin Wang, Qian Chu.

   PURPOSE: Tumor cells reprogram their fatty acid metabolism to meet the demands for their rapid proliferation. However, the interplay between fatty acid metabolism and the tumor microenvironment (TME) in lung cancer remains poorly defined. This study aims to elucidate how arachidonic acid (AA) metabolism, specifically via the enzyme 5-lipoxygenase (ALOX5), modulates anti-tumor immunity in non-small cell lung cancer (NSCLC).
METHODS: Data from public transcriptomic datasets were analyzed to identify differentially expressed and immune regulatory fatty acid metabolism-related genes in NSCLC. Spatial correlation between ALOX5 expression and CD8⁺ T cell infiltration was assessed via immunofluorescence. Functional impacts of ALOX5 on tumor growth, immune recruitment, and immunotherapy response were characterized using knockdown and overexpression models. Clinical relevance was evaluated by profiling plasma fatty acids via mass spectrometry in immunotherapy-treated cohorts.
RESULTS: Bioinformatic analysis nominated ALOX5-mediatedAA metabolic pathway as a key regulator of immune infiltration. Genetic knockdown of ALOX5 accelerated tumor progression, attenuated CD8⁺ T cell recruitment, and reduced leukotriene B4 (LTB4) production alongside downregulation of cytotoxic (granzymes) and chemotactic genes. Conversely, ALOX5 overexpression suppressed tumor growth and synergized with anti-PD-1 therapy. Exogenous AA supplementation similarly potentiated the efficacy of PD-1 blockade in vivo. Clinically, elevated plasma levels of AA and linoleic acid correlated with improved immunotherapy response and survival outcomes.
CONCLUSION: Tumor-intrinsic ALOX5 is a novel tumor suppressor that orchestrates CD8⁺ T infiltration via the AA-LTB4 axis in NSCLC. Our findings establish ALOX5-mediated AA metabolism as a therapeutically targetable pathway to overcome immunotherapy resistance, positioning dietary AA supplementation as a promising adjunctive strategy.
CLINICAL TRAIL NUMBER: Not applicable.

Keywords:  ALOX5; Arachidonic acid; Fatty acid; Immunotherapy

DOI:  https://doi.org/10.1007/s13402-025-01124-y
Cancer Res Treat. 2025 Nov 03.

PHF10 is a Novel Substrate of Keap1 to Protect Non-Small-Cell Lung Cancer (NSCLC) Cells Against Oxidative Stress and Confer Ferroptosis Resistance.

Xuan Lu, Ningning Kang, Yajun Chen, Xinru Zhao, Donglin Zhu, Jun Yang, Yong Yang, Hongya Xie.

   Purpose: Keap1 mutations mainly caused NRF2-dependent anti-oxidative stress responses, yet whether there are other downstream substrates and pathways remains unknown. This study aimed to uncover the role of Keap1 mutations in regulating PHF10-NRF2 axis in NSCLC and ferroptosis evasion.
Materials and Methods: Tandem affinity purification with mass spectrometry was used to screen peptides. Co-IP and ubiquitination assays were used to confirm the Keap1-PHF10 axis. A series of analyses in cell lines, patient samples, and xenograft models were conducted to uncover the functional dependency between Keap1 and NRF2. Transmission electron microscope was used to detect mitochondrion swelling under ferroptosis.
Results: Here, we reported that Keap1 binds and promotes polyubiquitination and degradation of PHF10, a subunit of the PBAF complex. NSCLC-associated Keap1 mutations are incapable of degrading PHF10, and thus induces PHF10 proteins stability. PHF10 ablation shows synthetic lethality in Keap1-deficient NSCLC cells. Mechanistically, PHF10 interacts with NRF2 to activate its downstream targets and enhance the NRF2-dependent anti-oxidative stress capacity in NSCLC. PHF10 recruits SMARCA2, one core cBAF subunit, to increase chromatin accessibility in NRF2-binding transcriptional regions. Cancer-associated Keap1 mutants confer resistance to ROS-induced cell death via accumulating PHF10-SMARCA2 complex. Increased PHF10 further induced ferroptosis resistance in Keap1-deficient NSCLC. Lastly, we utilized one small molecule inhibitor, SMARCA2-IN-8, to inhibit progression of Keap1-deficient NSCLC murine models.
Conclusion: Together, our study highlight the synthetic lethal relationship between Keap1 and PHF10, and provide targeting PHF10-SMARCA2 complex as an effective option to hit Keap1-deficient NSCLC.

Keywords:  Ferroptosis; Keap1; Lung neoplasms; NRF2; PHF10; Ubiquitination

DOI:  https://doi.org/10.4143/crt.2025.635
Anal Biochem. 2025 Nov 04. pii: S0003-2697(25)00246-5. [Epub ahead of print] 116007

The role of tyrosine metabolism-associated genes in predicting lung adenocarcinoma prognosis and their clinical relevance.

Wenxia Zhang, Guimei Wang, Zhenyu Wang, Guoqi Zhou, Hanliang Jiang.

   BACKGROUND: Tyrosine metabolism (TM) plays an important role in the progression of cancer, but its role in lung adenocarcinoma (LUAD) is still unclear. This study aims to construct TM-related prognostic features for LUAD.
METHODS: Transcriptomes and clinical data of LUAD were collected from public databases. A TM-related risk score (TMRS) model was constructed using 42 TM-related genes (TMRGs). The prognostic value of the model was comprehensively analyzed through survival analysis, enrichment analysis, immune assessment, and drug sensitivity prediction. The expression of key genes was also verified in LUAD cell lines and patient PBMCs.
RESULTS: A 14-gene prognostic model (TMRS) was constructed. TMRS was an independent prognostic factor for LUAD. The low TMRS group has a more active immune microenvironment and may be more sensitive to immunotherapy. Patients with high TMRS may be more sensitive to various chemotherapy drugs. The model genes were specifically expressed in different cell types, suggesting that they may be involved in metabolic reprogramming and tumor progression.
CONCLUSION: This study establishes a foundation for personalized risk assessment and treatment decisions in LUAD, highlighting the prognostic significance of TM.

Keywords:  biomarkers; immune infiltration; lung adenocarcinoma; prognosis; tyrosine metabolism

DOI:  https://doi.org/10.1016/j.ab.2025.116007
Discov Oncol. 2025 Nov 06. 16(1): 2048

Proteome-wide Mendelian randomization and colocalization analysis uncovers druggable targets for lung cancer across multiple phenotypes and complications.

Yunpeng Chen, Xiaohong Dai, Peng Zhang, Lijuan Yao, Qing Wang, Zhihong Qin, Tianmin Gao, Junguo Zhang.

   BACKGROUND: Lung cancer remains a leading cause of cancer-related mortality, necessitating novel therapeutic targets. The plasma proteome represents a key source for such targets.
METHODS: Proteome-wide Mendelian randomization (MR) and colocalization analyses were conducted to assess the causal effects of plasma proteins on lung cancer subtypes and complications. Genetic instruments (cis-pQTLs) for 2,090 proteins were derived from plasma proteome data (54,306 UK Biobank and 35,559 Icelandic participants). Lung cancer phenotype data were obtained from FinnGen R10.
RESULTS: MR identified seven plasma proteins showing significant causal associations with specific lung cancer phenotypes: high GGT1 increased non-small cell lung cancer (NSCLC) risk (OR 1.27, 95% CI 1.10-1.46; PFDR = 0.0261), GFRA2 increased the SCLC risk (OR 1.65, 95% CI 1.24-2.21; PFDR = 0.0462), and higher advanced glycosylation end-product specific receptor reduced the squamous cell carcinoma risk (OR 0.338 per SD increase, 95% CI 0.209-0.548; PFDR = 0.0138). Fifteen proteins showed associations with lung cancer complications. Colocalization strongly supported causal roles for eight proteins: FKBP1B (OR 1.15, 95% CI 1.09-1.22; PFDR = 0.00264), F11(OR 1.01, 95% CI 1.01-1.01; PFDR = 1.47 × 10- 23), ABO (OR 1.11, 95% CI 1.06-1.21; PFDR = 5.82 × 10- 9), F2 (OR 3.04, 95% CI 1.74-5.31; PFDR = 0.0102), and VSIG10L (OR 1.006, 95% CI 1.00-1.01; PFDR = 0.0159).
CONCLUSION: This study reveals causal proteins for various lung cancer phenotypes and complications, emphasizing causal pathways and potential therapeutic targets for lung cancer and providing new insights into its etiology, prevention, treatment, and therapy.

Keywords:  Lung cancer; Mendelian randomization; Proteome-wide analysis; Therapeutic targets

DOI:  https://doi.org/10.1007/s12672-025-03910-4