bims-meluca 2025-08-24 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–08–24
ten papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

KEAP1 mutations activate the NRF2 pathway to drive cell growth and migration, and attenuate drug response in thyroid cancer.
Association between sarcopenia and components of metabolic syndrome among Chinese older adults: a population-based longitudinal study using CHARLS.
Targeting FSP1 triggers ferroptosis in lung cancer.
The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.
CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis.
Exosomal FGD5-AS1 promotes proliferation of lung cancer cells under hypoxia by inhibiting miR-1179 and activating P-cadherin.
Atorvastatin exhibits anticancer effects by inhibiting YAP/TAZ activity in mesenchymal-like non-small cell lung cancer.
RUNX2 stimulates BMP8A to facilitate fatty acid metabolism and cause osimertinib resistance in lung adenocarcinoma.
Elevated Polyamine Metabolism Activates Fibroblasts via GCN2 Activation and Generates Senescent Fibroblasts to Promote Tumor Formation and Progression.
NK cell-derived extracellular vesicles enhance cytotoxicity and immune cell recruitment in non-small cell lung cancer.

bioRxiv. 2025 Aug 13. pii: 2025.08.13.670155. [Epub ahead of print]

KEAP1 mutations activate the NRF2 pathway to drive cell growth and migration, and attenuate drug response in thyroid cancer.

Nicholas E Bambach, Julio C Ricarte-Filho, Erin R Reichenberger, Christian Hernandez-Padilla, Kyle Hinkle, Amber Isaza, Andrew J Bauer, Aime T Franco.

The KEAP1/NRF2 pathway, a major regulator of the cellular oxidative stress response, is frequently activated in human cancers. Often mediated by loss-of-function mutations in KEAP1 , this activation causes increased NRF2 transcriptional activity and constitutive activation of the antioxidant response. While KEAP1 mutations have been well documented in various cancers, their presence and role in thyroid carcinoma have remained largely unexplored. In this study, we sequenced pediatric thyroid tumors and analyzed publicly available datasets, identifying 81 KEAP1 mutations in tumors across a range of histologies. In these tumors, we further identified frequent biallelic loss of KEAP1 via 19p13.2 loss of heterozygosity (LOH). MAPK-activating alterations were found in a subset of KEAP1 -mutant cases, but they were mutually exclusive with 19p13.2 LOH. Transcriptome analysis also revealed significant activation of the NRF2 pathway in KEAP1- mutant tumors. Four additional cases with similar transcriptional profiles but lacking mutational data were identified, likely representing putative KEAP1 mutants. Using in vitro cell line models, we then profiled the functional consequences of KEAP1 knockout in cells with and without known driver alterations. In these models, we show that KEAP1 loss leads to an NRF2-dependent upregulation of AKR1C3, GCLC, NQO1 , along with increased proliferation and migration, irrespective of MAPK mutational status. We also demonstrate that loss of KEAP1 reduced sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this report, we comprehensively profile KEAP1 mutations in thyroid tumors, showing they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as potential novel oncogenic drivers in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks.

DOI: https://doi.org/10.1101/2025.08.13.670155
BMC Public Health. 2025 Aug 18. 25(1): 2823

Association between sarcopenia and components of metabolic syndrome among Chinese older adults: a population-based longitudinal study using CHARLS.

Wenjing Tang, Jiaojiao Yu, Kefeng Yang, Jie Jia, Xuanxia Mao, Fangfang Song.

   BACKGROUND: Sarcopenia is an age-related loss of muscle mass and strength that affects quality of life in older adults and may also increase the risk of developing metabolic syndrome (MetS) and its components. This study aimed to explore the longitudinal association between sarcopenia and the components of MetS. Data for this study were derived from China Health and Retirement Longitudinal Survey (CHARLS).
METHODS: The sample included 3,758 participants aged ≥ 60 years who were included in the baseline survey of CHARLS (2011) and followed up until 2015. Sarcopenia status was defined according to the 2019 Asian Working Group for Sarcopenia (AWGS2019). The diagnostic components of MetS were assessed according to the clinical criteria outlined in the 2022 expert consensus on the management of MetS in older adults in China. Cox proportional hazards regression (HR) models were used to evaluate the effect of sarcopenia the risk factors of MetS.
RESULTS: In this study, 1,252 individuals with sarcopenia and 2,506 individuals without sarcopenia were included. During follow-up, 489 MetS cases were observed among those without MetS at baseline. Participants with sarcopenia exhibited significantly lower body mass index (BMI), waist circumference, triglycerides (TG), and blood glucose levels (all p < 0.001) compared to those without sarcopenia. After adjusting for sex, age, education, marital status, smoking, alcohol consumption, and physical activity, hazard ratios (HR) in the sarcopenia group were significantly elevated for abdominal obesity (HR 8.24, 95% CI 6.56-10.27; p < 0.001), hypertriglyceridemia (HR 2.12, 95% CI 1.40-3.20; p < 0.05), and MetS (HR 5.33, 95% CI 4.01-7.08; p < 0.001). In the BMI subgroup, the risk of sarcopenia was found to increase in elderly individuals within the low BMI of 18.5-23.9 kg/m2 (HR 5.16, 95% CI: 4.91-5.36; p < 0.001) and < 18.5 kg/m2 (HR 6.06, 95% CI: 5.98-6.51; p < 0.001).
CONCLUSION: Sarcopenia was significantly associated with specific components of MetS, particularly abdominal obesity and hypertriglyceridemia. In addition, low BMI emerged as a key factor related to sarcopenia development among older adults.

Keywords:  CHARLS; Chinese older individuals; Metabolic syndrome; Sarcopenia

DOI:  https://doi.org/10.1186/s12889-025-24090-4
bioRxiv. 2025 Aug 11. pii: 2025.08.07.668766. [Epub ahead of print]

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.

Pre-clinical and clinical studies have demonstrated how dietary antioxidants or mutations activating antioxidant metabolism promote cancer, highlighting a central role oxidative stress in tumorigenesis. However, it is unclear if oxidative stress ultimately increases to a point of cell death. Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, it remains unknown whether ferroptosis is a barrier to tumorigenesis and if it can be leveraged therapeutically. Using genetically-engineered mouse models (GEMMs) of lung adenocarcinoma (LUAD), we performed tumor specific loss-of-function studies of the two key ferroptosis suppressors, glutathione peroxidase 4 ( Gpx4 ) and ferroptosis suppressor protein 1 ( Fsp1 ), and observed increased lipid peroxidation, ferroptosis and robust suppression of tumorigenesis, suggesting that lung tumors are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was selectively 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 (Fsp1 KO ) tumors had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary, or pharmacological approaches effectively restored the growth of Fsp1 KO tumors in vivo . Unlike GPX4 , FSP1 expression was prognostic for disease progression and poorer survival in LUAD patients, highlighting its potential as a viable therapeutic target. Moreover, given the critical role of GPX4 in multiple tissues, there is a greater therapeutic window for targeting FSP1. 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 to improve disease outcome in lung cancer patients.

DOI: https://doi.org/10.1101/2025.08.07.668766
Cell Death Discov. 2025 Aug 19. 11(1): 390

The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.

Xing Yan, Changhong Liu.

At the center of tumor(neoplasm) metabolic adaptation lies activating transcription factor 4 (ATF4), a key regulator that orchestrates Glutamine (Gln) uptake, utilization, and redox balance under conditions of nutrient deprivation and oxidative stress. This review explores how ATF4 integrates environmental and cellular stress signals to drive Gln metabolic processes, enabling tumor survival, metabolic reprogramming, and immune evasion. The ATF4-Gln axis emerges as a pivotal vulnerability in cancer metabolic processes. Preclinical studies of small-molecule inhibitors and synthetic derivatives disrupting this pathway show promising results. Understanding the intricate interplay between ATF4, Gln metabolic processes, and cancer progression provides valuable insights for novel therapeutic strategies. Future research must address tumor heterogeneity and metabolic flexibility to fully harness the potential of ATF4-centered therapies. However, challenges such as off-target effects of ATF4 inhibitors and metabolic plasticity in tumors remain critical barriers. Future studies integrating multi-omics approaches and AI-driven drug discovery are warranted to overcome these hurdles.

DOI: https://doi.org/10.1038/s41420-025-02683-7
Pharmacol Res. 2025 Aug 14. pii: S1043-6618(25)00336-6. [Epub ahead of print] 107911

CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis.

Chunyu Hua, Guohui Zhang, Wendan Yu, Jie Zhou, Liyuan Ru, Guoqing Xue, Lina Zheng, Meiyi Wang, Yiwei Wang, Dianlin Yu, Qijing Wang, Jiaxin Liu, Ruonan Wang, Wuguo Deng, Ranran Tang, Wei Guo.

  A key factor that limits the therapeutic benefits for non-small cell lung cancer (NSCLC) patients is chemoresistance. Even so, a detailed understanding of the process involved in chemoresistance acquisition and development at molecular level in NSCLC is still lacking. Here, we established chemo-resistant NSCLC cells with obvious resistance to vincristine and paclitaxel and found the abnormal up-regulation of Carnitine O-Octanoyltransferase (CROT) in these cells by means of transcriptomics. In vitro and in vivo experiments demonstrate that the survival of NSCLC cells, especially chemosensitivity, including sensitivity to chemotherapeutics beyond vincristine and paclitaxel, was markedly influenced by CROT expression, and CROT silencing even reversed chemoresistance in NSCLC. Mechanistically, CROT is overactivated within peroxisomes in chemo-resistant NSCLC cells and drives chemoresistance relying on its involvement in lipid metabolism and oxidative stress processes. By mediating the production of Hydrogen Peroxide (H2O2) and reactive oxygen species (ROS), CROT stabilizes eryth-like-2 associated factor 2 (Nrf2) via preventing its ubiquitination and degradation, leading to more nuclear translocation of Nrf2, thereby inhibiting chemotherapy stress-induced ferroptosis. Accordingly, fatty acid oxidation inhibitors or ferroptosis activators rendered NSCLC cells increased sensitivity to chemotherapy in vitro and in vivo. Clinically and encouragingly, the aberrant up-regulation of CROT and Nrf2 was observed in chemo-resistant NSCLC tumor tissues and patients with higher CROT and/or Nrf2 level possessed a poor outcome. In sum, our study identifies CROT as a key promoter to drive chemoresistance of NSCLC cells by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis. The targeted inhibition of this axis and associated components individually or in cascades combined with chemotherapy may be exploited in avoiding or overcoming chemoresistance in NSCLC.

Keywords:  3-Methyladenine (PubChem CID: 135398661); CROT; Chemoresistance; Cisplatin (PubChem CID: 5460033); Erastin (PubChem CID: 11214940); Ferroptosis; Ferrostain-1 (PubChem CID: 4068248); Gemcitabine (PubChem CID: 60750); NSCLC; Necrostatin-1 (PubChem CID: 2828334); Nrf2; Paclitaxel (PubChem CID: 36314); Peroxisomes; Vincristine (PubChem CID: 5978); Z-VAD-FMK (PubChem CID: 5737)

DOI:  https://doi.org/10.1016/j.phrs.2025.107911
Hum Cell. 2025 Aug 17. 38(5): 145

Exosomal FGD5-AS1 promotes proliferation of lung cancer cells under hypoxia by inhibiting miR-1179 and activating P-cadherin.

Bilan Yang, Zhongkun Tian, Zhiqiang Luo, Yi Yuan, Qiang Wen, Zhihua Liu.

  Lung adenocarcinoma (LUAD) continues to be a major contributor to cancer-related deaths due to its aggressive nature and resistance to current therapies, highlighting the need for novel molecular insights and therapeutic targets. This study investigated the function of exosomal lncRNA FGD5-AS1 in lung adenocarcinoma (LUAD) and its interaction with miR-1179 and CDH3. We discovered that FGD5-AS1 was substantially overexpressed in LUAD cells and exosomes under hypoxic conditions, while miR-1179, a tumor suppressor, directly targeted and downregulated CDH3. By sponging miR-1179, FGD5-AS1 serves as a competing endogenous RNA (ceRNA) to prevent the suppression of CDH3, thereby promoting LUAD cell growth, movement, and infiltration. It was demonstrated that knockdown of FGD5-AS1 or overexpression of miR-1179 significantly reduced tumor growth in vivo. These results demonstrate a novel exosome-mediated regulatory axis, suggesting that targeting the FGD5-AS1/miR-1179/CDH3 pathway could offer new therapeutic strategies for LUAD.

Keywords:  Exosome; Hypoxia; LncRNA FGD5-AS1; Lung adenocarcinoma; MiR-1179; P-cadherin

DOI:  https://doi.org/10.1007/s13577-025-01261-4
Sci Rep. 2025 Aug 18. 15(1): 30167

Atorvastatin exhibits anticancer effects by inhibiting YAP/TAZ activity in mesenchymal-like non-small cell lung cancer.

Takuro Ishikawa, Tomohito Okubo, Natsuki Matsushita, Jiro Tashiro, Katsuhiko Warita, Munekazu Naito.

  Non-small cell lung cancer (NSCLC) accounts for most lung cancer diagnoses. Statins preferentially inhibit the proliferation of mesenchymal- over epithelial-like cells in various types of cancer, including NSCLCs. However, the mechanisms underlying the differential statin sensitivity of mesenchymal and epithelial cancer cells remain unknown. Statins inhibit YAP/TAZ, effectors of the Hippo pathway, via depletion of geranylgeranyl pyrophosphate. Here, we aimed to elucidate the mechanisms underlying statin sensitivity in mesenchymal cancer. We explored the anticancer effects of atorvastatin and its association with YAP/TAZ activity in NSCLC cell lines with different epithelial-mesenchymal phenotypes. Atorvastatin significantly reduced the proliferation, migration, and invasion of mesenchymal-like cells, while showing negligible effect on epithelial-like cells. Atorvastatin also inhibited YAP/TAZ nuclear localization and downstream gene expression in mesenchymal cells but did not affect epithelial cells. Small interfering (si) RNA-mediated inhibition of both YAP and TAZ reduced the proliferation of all NSCLC cell lines tested, regardless of phenotype, indicating that sensitivity to YAP/TAZ inhibition and statins differ. In summary, our results suggest that inhibited YAP/TAZ nuclear localization by statins differs between epithelial and mesenchymal NSCLC cell lines, resulting in differential statin sensitivity.

Keywords:  Mesenchymal cancer cells; Non-small cell lung cancer; Statins; TAZ; YAP

DOI:  https://doi.org/10.1038/s41598-025-15624-2
Physiol Int. 2025 Aug 18.

RUNX2 stimulates BMP8A to facilitate fatty acid metabolism and cause osimertinib resistance in lung adenocarcinoma.

Yilai Yu, Lifei Huang, Xingxing Zhu, Yahong Sun.

   Background: The most prevalent form of lung cancer, lung adenocarcinoma (LUAD), has significant incidence and fatality rates worldwide. When treating LUAD, osimertinib resistance is a typical problem. Thus, it is imperative to address the concerns of clarifying the mechanism of osimertinib resistance in LUAD and enhancing medication sensitivity.
Methods: Using bioinformatics techniques, expression and possible biological roles of BMP8A in LUAD were examined, and predictions were made about upstream regulatory variables and binding locations. H1975 cell line, resistant to osimertinib, was created. Western blot and RT-qPCR were instrumental to determine mRNA and protein expression of FABP5, ACC1, and FASN associated to lipid metabolism. A fluorescent lipid synthesis test kit was utilized to detect amount of triglycerides present in culture medium. BMP8A and RUNX2 mRNA levels were assayed using RT-qPCR. Utilizing CCK-8 and ANNEXIN V-FITC/PI flow cytometry, cell viability was assessed. Through the use of dual luciferase assays, whether RUNX2 could regulate BMP8A was confirmed. CHIP was further employed to confirm whether the two were bound together.
Results: BMP8A and fatty acid metabolism (FAM) have a strong association, as revealed by bioinformatics investigation, and RUNX2 is its upstream transcription factor. Osimertinib-resistant H1975 cell lines were successfully created, and these cell lines showed a significant upregulation of BMP8A expression. The drug sensitivity of the resistant cell lines was decreased, and their FAM level was considerably enhanced by overexpressing BMP8A. Changes in drug sensitivity and FAM were reversed by using FAM inhibitors. An efficient binding of RUNX2 to the BMP8A promoter region was demonstrated by experimental validation, hence activating the production of the BMP8A gene. Lowering LUAD cell survival rates, lipid metabolism levels, and BMP8A expression were all caused by RUNX2 knockdown.
Conclusion: RUNX2 activated BMP8A-mediated FAM to facilitate osimertinib resistance in LUAD.

Keywords:  BMP8A; fatty acid metabolism; lung adenocarcinoma; osimertinib resistance

DOI:  https://doi.org/10.1556/2060.2025.00482
Mol Carcinog. 2025 Aug 19.

Elevated Polyamine Metabolism Activates Fibroblasts via GCN2 Activation and Generates Senescent Fibroblasts to Promote Tumor Formation and Progression.

Eric T Alexander, Katherine S Barone, Susan K Gilmour.

  GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine in the tissue microenvironment activates GCN2 and alters stromal cell metabolism to support tumor cell survival and drive myeloid immunosuppressive function. To study the effect of elevated polyamine metabolism on fibroblast activation, we used the K6/ODC transgenic model of carcinogen-initiated, polyamine-promoted skin carcinogenesis. GCN2 loss significantly delayed tumor development and decreased tumor number and tumor burden in K6/ODC; GCN2-/- mice compared that in K6/ODC mice. Underlying dermal fibroblasts from nontumor bearing K6/ODC mice express elevated levels of genes associated with GCN2 activation and fibroblast activation. Expression of these genes was not elevated in K6/ODC; GCN2-/- dermis. In addition, K6/ODC mice have significantly more myeloid derived suppressor cells (MDSC) compared to normal littermates, and MDSCs were decreased in K6/ODC mice deficient in GCN2. Dermal fibroblasts cultured from K6/ODC transgenic mouse skin secrete increased levels of protumorigenic factors including senescence associated secretory phenotype (SASP) factors that stimulate invasiveness of stem-like epidermal tumorspheres as well as the polarization of M2-like macrophages. Using K6/ODC; p16-3MR mice in which senescent fibroblasts can be eliminated with ganciclovir treatment, carcinogen-initiated tumor development was greatly inhibited when senescent fibroblasts were eliminated in K6/ODC; p16-3MR mice. Our studies suggest a new paradigm in which cellular stress responses resulting from increased polyamine biosynthesis accelerate fibroblast activation and a senescence phenotype to create a protumorigenic microenvironment.

Keywords:  GCN2; activated fibroblasts; polyamines; senescence; skin tumor promotion

DOI:  https://doi.org/10.1002/mc.70034
Front Immunol. 2025 ;16 1633010

NK cell-derived extracellular vesicles enhance cytotoxicity and immune cell recruitment in non-small cell lung cancer.

Joanna Palade, Eric Alsop, Nanyun Tang, Jerry Antone, Dorothy M Paredes, Tithi Ghosh Halder, Raffaella Soldi, Taylor Bargenquast, Gary Schwartz, Jennifer Finholt, George J Snipes, Sunil Sharma, Michael Berens, Timothy G Whitsett, Kendall Van Keuren-Jensen, Ronan J Kelly.

   Introduction: Immune-based agents, especially Immune Checkpoint Inhibitors (ICI), are standard of care therapy in non-small cell lung cancers (NSCLC); however, a significant number of patient tumors fail to respond, or develop resistance. While target expression, mutation burden and oncogenic pathways impact responses, an established mechanism contributing to ICI therapy failure is evasion of T-cell responses via downregulation of human leukocyte antigen (HLA). Conversely, natural killer (NK) cells eQector function is enhanced in the absence of HLA, making NK cellular therapies an attractive option for ICI resistant tumors. Challenges for current NK cell therapies include failure to adequately infiltrate solid tumors and long-term persistence, which may be overcome by deploying NK-derived extracellular vesicles (NKEVs) as a personalized novel adoptive cellular therapeutic with cytotoxic effects.
Methods: In a human NSCLC cohort (n=10), we used single cell RNAseq and antibody labeling (CITEseq) to examine the immune cell landscape in peripheral immune cells (PBMCs) and tumors. NKEVs retrieved from patient NK cells were characterized with proteomics and bulk RNAseq, and EV functionality was assessed using primary tumor organoids.
Results: We identified circulating NK cell subsets, describing diQerences in cell composition, gene expression and signaling, related to time point, NSCLC subtype (adenocarcinoma, squamous cell), composition and tumor grade. Next, we examined the functional capabilities of patient NKEVs in organoid structures derived from primary tumor cells, finding that exposure to patient NKEVs resulted in a 40-45% decrease in organoid viability, and significantly lowered the cisplatin dose required to elicit cytotoxicity. In Nivolumab treated PBMC co-culture experiments, NKEV addition favorably shifted the organoid infiltrating immune population to significantly fewer CD4+ T cells and more CD56+ NK cells. Finally, we used the multi-omic characterization of NKEV molecular cargo to identify RNA transcripts and proteins associated with cytotoxic and immune recruiting functions.
Conclusions: This work demonstrated that NKEVs can be successfully harvested from patient derived, expanded NK cells, and highlights their heterogeneous cargo, and anti-tumor properties in combination with standard-of-care therapies.

Keywords:  CITE-seq; NKEVs; NSCLC; extracellular vesicles; lung cancer; transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2025.1633010