bims-meluca 2026-07-12 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–07–12
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

A Prospective Observational Study of Anamorelin During Chemoimmunotherapy in Non-Small Cell Lung Cancer With Cachexia (SPIRAL-ANA).
Circulating metabolites in plasma reveal potential target of lung cancer prevention: insights from fatty acids pathway.
KLF5-driven TAZ-FASN signaling reprograms fatty acid metabolism to support Treg differentiation in lung cancer.
Identifying markers of cachexia and nutritional deficit on radical radiotherapy outcomes in lung and head and neck cancer.
De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.
Inhibition of ferroptosis via SLC25A39-NRF2 axis drives Osimertinib resistance in lung adenocarcinoma.
Body mass index and fasting insulin predict survival and EGFR-TKI benefit in Stage IV lung adenocarcinoma.
Lower blood glucose levels (HbA1c) within the non-diabetic range are associated with improved survival in patients diagnosed with lung, colon and ovarian cancer: an explorative study.
The mechanism of deubiquitinase USP14 modifying HSP90AA1 to activate NRF2 signaling in lung cancer cell resistance to ferroptosis.

J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70340

A Prospective Observational Study of Anamorelin During Chemoimmunotherapy in Non-Small Cell Lung Cancer With Cachexia (SPIRAL-ANA).

Kenji Morimoto, Junji Uchino, Makoto Hibino, Yuki Takeyasu, Ken Yamamoto, Yoshie Morimoto, Yusuke Chihara, Takayuki Nakano, Hiroyasu Kaneda, Shunya Tanaka, Shinsuke Ogusu, Yasuhiro Goto, Takashi Nomizo, Takayo Ota, Hiroaki Tsukamoto, Yoshizumi Takemura, Katsumi Nakatomi, Hayato Koba, Kohei Yoshimine, Takayuki Shimose, Tadaaki Yamada, Koichi Takayama.

   BACKGROUND: The prognosis of patients with advanced non-small cell lung cancer (NSCLC) complicated by cancer cachexia remains poor. Anamorelin, a ghrelin receptor agonist, has been approved only in Japan for the treatment of cancer cachexia.
METHODS: This prospective multicentre observational study was conducted to evaluate the impact of anamorelin administration on the efficacy and safety of chemoimmunotherapy in patients with NSCLC and cancer cachexia. The primary endpoint was progression-free survival (PFS), evaluated against a predefined threshold derived from a previous retrospective cohort of patients with cachectic NSCLC treated with chemoimmunotherapy alone. This study was registered in the Japan Registry of Clinical Trials (jRCT1071210053).
RESULTS: Between August 2021 and January 2024, 123 patients were enrolled from 29 institutions in Japan, with 114 included in the full analysis set. The median age was 73 years; 28 (24.6%) were female and 20 patients (17.5%) had a performance status of 2. The objective response rate was 57.9% (95% confidence interval [CI]: 48.7%-66.6%). Median PFS and overall survival (OS) were 6.2 months (95% CI: 4.6-7.7) and 18.5 months (95% CI: 13.1-28.6), respectively. The lower limit of the 95% CI for PFS did not exceed the predefined threshold of 5 months. At week 12, 61 of 85 patients (71.8%) had transitioned from cancer cachexia to a non-cachectic state. Landmark survival analyses at week 12 showed that patients who achieved this transition had significantly longer OS compared with those who remained cachectic (19.9 vs. 7.1 months; hazard ratio for cachexia vs. transition, 2.19; 95% CI: 1.19-4.02; p = 0.0098). Grade ≥ 3 hyperglycemia was observed in six patients (5.1%), but no new safety signals were identified.
CONCLUSIONS: Anamorelin combined with chemoimmunotherapy did not prolong PFS in advanced NSCLC with cancer cachexia, but achieved a high rate of cachexia reversal. Transition to a non-cachectic state was associated with improved OS, suggesting that cachexia reversal may serve as a surrogate for survival benefit.
TRIAL REGISTRATION: jRCT1071210053 (jRCT).

Keywords:  anamorelin; cancer cachexia; chemoimmunotherapy; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/jcsm.70340
Nutr J. 2026 Jul 08.

Circulating metabolites in plasma reveal potential target of lung cancer prevention: insights from fatty acids pathway.

Yunyun Liu, Qinghan Liu, Tong Sun, Honghao Yang, Zheng Ma, Liuxin Li, Chao Ji, Huanhuan Chen, Yang Xia.

   BACKGROUND: Prospective evidence regarding the associations between circulating fatty acids (FAs) and lung cancer risk-particularly regarding their interplay with exposome factors and genetic susceptibility-remains limited. Furthermore, the predictive utility of FAs as biomarkers for lung cancer has not been fully characterized. Therefore, this study aims to evaluate the associations of circulating FAs metabolism with lung cancer risk, focusing on their interactions with smoking and genetic risk profiles, while further assessing their potential as predictive biomarkers.
METHODS: A total of 107,954 participants from the UK Biobank study were included in analyses. The associations of circulating FAs, as well as their interactions with polygenic risk score (PRS), smoking status, and FA-related genetic variants, with lung cancer were examined. The differential expression of genes and hub gene involved in FAs metabolism in lung cancer were explored using RNA-sequencing data from The Cancer Genome Atlas. 10-year lung cancer risk prediction models were developed and evaluated incorporating FAs, PRS, and traditional risk factors.
RESULTS: A total of 965 lung cancer cases occurred during a mean follow-up of 12.12 years. Circulating saturated FAs (SFAs), monounsaturated FAs (MUFAs) and n-6/n-3 PUFAs ratios were positively associated with lung cancer, whereas polyunsaturated FAs (PUFAs)/n-3 PUFAs were negatively associated with the outcome (all P for trend < 0.05). Moreover, specific FAs presented significant interaction effects with smoking history, lung cancer-PRS, and FAs-associated alleles on the risk of lung cancer. RNA-sequencing of tumor and normal tissue indicated differential gene expression on FAs metabolism (FDR < 0.05). Models incorporating FAs and traditional risk factors significantly improved lung cancer risk prediction, achieving an area under the curve of 0.788.
CONCLUSION: Our study identifies significant associations between circulating FAs and lung cancer, characterized by interplays with smoking and genetic risk profiles. These metabolic markers provide incremental predictive value, offering new insights into risk stratification and individualized lung cancer prevention.

Keywords:  Association; Circulating fatty acids; Lung cancer; Prediction

DOI:  https://doi.org/10.1186/s12937-026-01355-1
J Transl Med. 2026 Jul 06.

KLF5-driven TAZ-FASN signaling reprograms fatty acid metabolism to support Treg differentiation in lung cancer.

Hongxiang Huang, Jinhong Chen, Peiyuan Zhong, Sujuan Peng, Qiuxa Zhong, Chenfeiyang Deng, Fen Wang, Zhihui Lu, Yangyang Liu, Li Chen.

   BACKGROUND: Metabolic reprogramming is a fundamental hallmark of cancer and provides essential biochemical support for malignant progression. In lung cancer, aberrant fatty acid metabolism not only fuels cancer cell growth but also influences regulatory T cell (Treg) differentiation through altered lipid availability. Krüppel-like factor 5 (KLF5) has been implicated in lung cancer progression; however, its role in coordinating cancer fatty acid metabolism and Treg differentiation remains insufficiently defined.
METHODS: We combined clinical lung cancer specimens, genetically modified lung cancer cell models, Treg differentiation systems, and mouse tumor models to define the metabolic function of KLF5. Gain- and loss-of-function approaches were used to determine how KLF5 affects lipid storage, fatty acid synthesis, extracellular free fatty acid production, and tumor growth. Conditioned-medium transfer experiments, fatty acid uptake assays, fatty acid oxidation measurements, and flow cytometry were applied to evaluate the impact of cancer cell-derived lipid output on Treg differentiation. Mechanistically, promoter-binding assays, transcriptional reporter analysis, protein-interaction experiments, molecular docking, and TAZ depletion were used to dissect how KLF5 regulates FASN-dependent fatty acid synthesis.
RESULTS: KLF5 was highly expressed in lung cancer tissues and cells and showed positive associations with lipogenic markers and Treg-related indicators. Suppression of KLF5 markedly weakened the fatty acid metabolic phenotype of lung cancer cells, as reflected by reduced lipid droplet accumulation, decreased free fatty acid release, and downregulation of FASN, SCD1, DGAT2, and PLIN5. In vivo, KLF5 knockdown restrained tumor growth and reduced fatty acid synthesis-related molecular features. Mechanistically, KLF5 bound directly to the FASN promoter and cooperated with TAZ to enhance FASN transcription. KLF5 promoted nuclear accumulation of TAZ, whereas TAZ silencing attenuated KLF5-induced FASN expression, lipid accumulation, and free fatty acid production. Functionally, fatty acids released from KLF5-overexpressing lung cancer cells enhanced CD36-associated fatty acid uptake and fatty acid oxidation in Tregs, thereby promoting Treg differentiation. Conversely, KLF5 depletion reduced this lipid-associated differentiation process both in vitro and in tumor-bearing mice.
CONCLUSION: This study reveals a KLF5-driven fatty acid metabolic program in lung cancer. KLF5 cooperates with TAZ to activate FASN transcription, thereby increasing lipogenesis and free fatty acid release. The resulting lipid output promotes CD36-dependent fatty acid uptake and oxidation in Tregs and supports their differentiation. These findings identify the KLF5-TAZ-FASN axis as a cancer metabolism-centered mechanism linking lung cancer lipogenesis to Treg differentiation, highlighting this pathway as a potential metabolic vulnerability for interfering with fatty acid-supported lung cancer progression.

Keywords:  FASN; Fatty acid metabolism; KLF5; Lung cancer; Metabolic reprogramming; Regulatory T cells; TAZ

DOI:  https://doi.org/10.1186/s12967-026-08557-5
Curr Opin Support Palliat Care. 2026 Jul 08.

Identifying markers of cachexia and nutritional deficit on radical radiotherapy outcomes in lung and head and neck cancer.

T K Liu, D Noble, M Stares, I Phillips.

   PURPOSE OF REVIEW: Cancer cachexia is a multifactorial syndrome characterised by weight loss, muscle wasting, malnutrition, and systemic inflammation. Although well-recognised in advanced cancer, its significance in patients receiving radical radiotherapy for potentially curable malignancies is less well understood. This review examines the impact of cachexia-related biomarkers in patients undergoing radical radiotherapy for lung or head and neck cancers.
RECENT FINDINGS: Many studies evaluating cachexia-related phenotypes do not explicitly use the term 'cachexia'. Therefore, this review focuses on four key domains of cachexia: weight loss, malnutrition, sarcopenia, and systemic inflammation. Across both tumour types, these biomarkers were frequently associated with poorer survival, increased treatment toxicity, and reduced treatment tolerance in patients receiving radical radiotherapy with curative intent for lung or head and neck cancers. However, the literature is dominated by retrospective studies employing heterogeneous definitions in poorly defined patient groups.
SUMMARY: Cachexia-related biomarkers provide important prognostic information in patients receiving radical radiotherapy for lung cancer and head and neck cancer. Routine assessment of weight loss, nutritional status, body composition, and systemic inflammation may improve risk stratification and support personalised treatment decisions. Future prospective studies should incorporate standardised cachexia assessments to validate their clinical utility and evaluate emerging nutritional, prehabilitation, and anti-cachexia interventions.

Keywords:  cancer cachexia; head and neck cancer; lung cancer; radiotherapy; systemic inflammation

DOI:  https://doi.org/10.1097/SPC.0000000000000818
Adv Sci (Weinh). 2026 Jul 07. e76202

De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.

Haitao Wang, Tianzhen Hua, Meiling Wang, Bingbing Meng, Yue Zhang, Chengxu Jiang, Yunhe Gao, Hongqi Yang, Jian Bo.

  Cancer-associated cachexia is a devastating syndrome characterized by progressive weight loss, reduced survival, and impaired responses to anticancer therapies. Growth differentiation factor 15 (GDF15), acting through its receptor GFRAL, has emerged as a key mediator of cachexia, yet effective and mechanistically defined strategies to neutralize this pathway remain limited. Here, we applied structure-guided de novo protein design to generate compact minibinders that selectively target the GDF15-GFRAL interaction interface. Using an integrated computational pipeline combining RFdiffusion, ProteinMPNN, and AlphaFold 3 structure prediction, we designed and experimentally validated high-affinity GDF15 minibinders with picomolar-range binding affinities and exceptional structural stability. Mutagenesis and charge-complementary rescue experiments confirm that these minibinders neutralize GDF15 through precisely engineered interface contacts. Functionally, the minibinders suppress GDF15-GFRAL signaling, inhibit downstream transcriptional responses, and robustly reverse cachexia in vivo across multiple tumor models, resulting in significant improvements in body weight and survival. Importantly, neutralization of GDF15 also restores sensitivity to anti-PD-1 immunotherapy in a GDF15-driven resistant tumor model. Combination treatment enhances CD8+ T cell infiltration and effector function within tumors, and its antitumor efficacy is strictly dependent on CD8+ T cells. Together, these findings demonstrate that de novo designed GDF15 minibinders can achieve potent, mechanism-defined neutralization of the GDF15-GFRAL axis in vivo, translating into robust physiological benefits and restoration of immunotherapy efficacy.

Keywords:  GDF15; RFdiffusion; cancer cachexia; de novo protein design; immune checkpoint blockade

DOI:  https://doi.org/10.1002/advs.76202
Cell Mol Life Sci. 2026 Jul 06.

Inhibition of ferroptosis via SLC25A39-NRF2 axis drives Osimertinib resistance in lung adenocarcinoma.

Kai Fu, Zhilin Zeng, Wenfeng Wang, Wei Wu, Yijie Gong, Xiangning Fu, Yixin Cai, Changyu Liu.

   OBJECTIVE: Overcoming resistance to Osimertinib remains a major clinical challenge in lung adenocarcinoma (LUAD). The molecular mechanisms driving this resistance are still not fully understood.
METHODS: Integrated bioinformatics analysis and functional assays were performed to investigate the role of SLC25A39 in LUAD progression and drug resistance. Mechanistic studies were conducted using co-immunoprecipitation and rescue experiments. Osimertinib-resistant cell models and xenograft assays were used to evaluate therapeutic responses.
RESULTS: SLC25A39 was significantly upregulated in LUAD and correlated with unfavorable patient outcomes. Functional studies showed that SLC25A39 depletion suppressed malignant phenotypes and enhanced ferroptosis, whereas its overexpression produced the opposite effects. Mechanistically, SLC25A39 was found to interact with NRF2 and was associated with increased NRF2 stability and transcriptional activity, leading to enhanced glutathione synthesis and attenuation of lipid peroxidation. Importantly, silencing SLC25A39 sensitized LUAD cells to Osimertinib. Consistent with this, pharmacological induction of ferroptosis using RSL3 markedly enhanced the antitumor effects of Osimertinib in both parental and resistant models, resulting in reduced tumor growth in vitro and in vivo, particularly in SLC25A39-high contexts.
CONCLUSION: SLC25A39 promotes LUAD progression and Osimertinib resistance by suppressing ferroptosis via NRF2. Targeting ferroptosis may represent a promising strategy to overcome Osimertinib resistance.

Keywords:  Chemotherapy resistance; Ferroptosis; Lung adenocarcinoma; Osimertinib; SLC25A39

DOI:  https://doi.org/10.1007/s00018-026-06313-y
Front Oncol. 2026 ;16 1742177

Body mass index and fasting insulin predict survival and EGFR-TKI benefit in Stage IV lung adenocarcinoma.

Huiru Guo, Lingshuang Liu, Jan P A Baak.

   Background: Obesity, hyperinsulinemia, and type 2 diabetes mellitus (T2DM) are considered adverse metabolic conditions in cancer, although exceptions like the "obesity paradox" have been reported. Their prognostic significance in advanced lung adenocarcinoma (LUAD), particularly in patients receiving tyrosine kinase inhibitor (TKI) therapy, remains unclear.
Methods: We prospectively analyzed 133 consecutive patients with newly diagnosed stage IV LUAD and ECOG performance status 0-1 enrolled between 2020 and 2024. All had ≥3 months of follow-up and T2DM status. BMI was available in 104 patients, glucose and fasting insulin in 46 patients. Primary endpoint was overall survival (OS), assessed using Kaplan-Meier and multivariable Cox regression. Propensity score and interaction analyses evaluated TKI, immune checkpoint inhibitor (ICI), and anti-VEGF therapies.
Results: High BMI, hyperglycemia, hyperinsulinemia, and T2DM were not associated with worse outcomes. In contrast, low BMI (<22.1 kg/m²; P = 0.007, HR 2.56, 95%CI 1.29 - 5.08) and low fasting insulin (≤34 pmol/L; P < 0.001, HR 10.02, 95%CI 2.73-36.8) were independently associated with shorter OS, while EGFR-TKI therapy was associated with improved survival (P = 0.02, HR 0.52). Patients with combined BMI <22.1 kg/m² and insulin <34 pmol/L also derived survival benefit from EGFR-TKI therapy; however, absence of EGFR-TKI in this subgroup was associated with very poor 3-year OS (35%). ICI and anti-VEGF outcomes were not significantly affected.
Conclusions: Low BMI and low fasting insulin identify a metabolically depleted subgroup with poor prognosis in stage IV LUAD, with worse outcomes observed in patients not receiving EGFR-TKI therapy. These parameters may improve risk stratification and support early nutritional and exercise-based interventions.

Keywords:  EGFR tyrosine kinase inhibitor; body mass index; cancer metabolism; fasting insulin (FINS); lung adenocarcinoma; non-small cell lung cancer; overall survival (OS time)

DOI:  https://doi.org/10.3389/fonc.2026.1742177
BMC Cancer. 2026 Jul 11.

Lower blood glucose levels (HbA1c) within the non-diabetic range are associated with improved survival in patients diagnosed with lung, colon and ovarian cancer: an explorative study.

Oliver Abrahamsen, Jakob Hagen Vasehus Schou, Jakob Sidenius Johansen, Mie Bejstrup Jensen, Jakob Lykke, Claus Høgdall, Esben Budtz-Jørgensen, Estrid Høgdall.

   BACKGROUND: Cancer cells increase their uptake and use of glucose to facilitate processes such as proliferation and metastasis development. It may therefore be speculated that the availability of glucose in the blood may influence cancer progression and impact clinical outcomes. This study exploratively investigated if blood glucose levels (HbA1c) were associated with overall survival, in an unselected population representing a real-world group of patients diagnosed with cancer.
METHODS: Between 2012 and 2017 a total of 296 patients diagnosed with lung (n = 99), colon (n = 98) and ovarian (n = 99) cancer were included. The patients were included from three clinical cohorts (the LUCAS cohort study (lung cancer), the REBECCA cohort study (colon cancer) and the Pelvic Mass/GOVEC study (ovarian cancer)) based on a few inclusion and exclusion criteria. HbA1c was measured using a blood sample taken during the course of treatment. Survival analysis was performed using the Kaplan-Meier method and multivariate Cox regression.
RESULTS: We observed that lower levels of blood glucose (HbA1c) were significantly associated with improved overall survival across the three different cancer types. In combined univariate analysis including all 296 patients, an HbA1c value < 40 mmol/mol (5.8%) was associated with a 5-year survival of 55.1%, whereas an HbA1c value ≥ 40 mmol/mol (5.8%) was associated with a 5-year survival of 27.0% (P-value < 0.0001). Furthermore, an HbA1c value within the interval (-inf, 30] mmol/mol ((-inf, 4.9%]) was associated with a 5-year survival of 66.7%, with increasing HbA1c intervals gradually correlating with decreased survival (P-value < 0.0001). Multivariate analysis maintained an HbA1c value < 40 mmol/mol (5.8%) as an independent factor with an estimated hazard ratio of 0.64 (95% CI 0.45, 0.91 P-value = 0.013).
CONCLUSIONS: These results raise the question whether HbA1c could serve as an important prognostic factor across multiple types of cancer, and whether therapeutically controlling the blood glucose level might potentially be beneficial. However, further studies are needed before definitive conclusions can be made.

Keywords:  Blood glucose; Cancer; Colon cancer; HbA1c; Lung cancer; Ovarian cancer; Survival

DOI:  https://doi.org/10.1186/s12885-026-16460-x
Mol Biol Rep. 2026 Jul 10. pii: 1131. [Epub ahead of print]53(1):

The mechanism of deubiquitinase USP14 modifying HSP90AA1 to activate NRF2 signaling in lung cancer cell resistance to ferroptosis.

Shengliang He, Qizhou Bai, Dacheng Jin, Zhou Chen, Yunjiu Gou.

  Objective The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) has been implicated in LC; however, its specific mechanism in lung cancer (LC) remains inadequately clarified. This study investigated the mechanism of USP14 modifying heat shock protein 90 alpha family class A member 1 (HSP90AA1) to activate nuclear factor erythroid-2 related factor 2 (NRF2) signaling in ferroptosis resistance of LC cells. Methods LC cell lines A549/H1299 were transfected with small-interfering (si)-USP14, oe-USP14, si-HSP90AA1, or oe-NRF2, followed by treatment with the ferroptosis inducer Erastin, the NRF2 inhibitor ML385, or the proteasome inhibitor MG132. Cell viability, USP14, HSP90AA1, NRF2, ferroptosis/oxidative stress-related protein expression, and lipid peroxidation were measured. Co-immunoprecipitation was used to examine USP14-HSP90AA1 interaction and HSP90AA1 ubiquitination. Cycloheximide chase assays and immunofluorescence were performed to assess HSP90AA1 stability and NRF2 nuclear translocation, respectively. Results USP14 knockdown markedly reduced cell viability in Erastin-treated LC cells, decreased solute carrier family 7 member 11/glutathione peroxidase 4 expression, and increased malondialdehyde, Fe2+, and reactive oxygen species levels while reducing glutathione and enhancing lipid peroxidation. Conversely, USP14 overexpression enhanced ferroptosis resistance. USP14 increased HSP90AA1 stability through deubiquitination, whereas HSP90AA1 silencing partially reversed USP14-mediated ferroptosis resistance. HSP90AA1 overexpression promoted NRF2 nuclear translocation. NRF2 inhibition enhanced ferroptosis and partially reversed USP14-induced ferroptosis resistance, whereas NRF2 overexpression partially reversed the promotion of ferroptosis induced by USP14 knockdown. Conclusion USP14 stabilizes HSP90AA1 through deubiquitination, thereby activating the NRF2 signaling pathway and consequently enhancing ferroptosis resistance in LC cells.

Keywords:  Deubiquitination; Ferroptosis; Heat shock protein 90 alpha family class A member 1; Lung cancer; Nuclear factor erythroid-2 related factor 2; Ubiquitin-specific protease 14

DOI:  https://doi.org/10.1007/s11033-026-12204-z