bims-meluca 2026-09-27 papers

Mol Cell Biochem. 2026 Sep 19.

Integrative multi-omics analysis identifies LIPA as a prognostic hub and ferroptosis regulator in lung adenocarcinoma.

Fan Zhang, Shuai Han, Xiaodong Cao, Dan Pan, Weijie Song.

Lung adenocarcinoma (LUAD) remains one of the leading causes of cancer mortality, underscoring the urgent need for biomarkers and therapeutic targets rooted in metabolic reprogramming. By integrating multi-omics analyses with experimental validation, we identified 67 lipid metabolism-related genes dysregulated in LUAD and constructed a five-gene prognostic signature via LASSO regression; lower expression of the signature genes correlated with poor survival. Single-cell and spatial transcriptomics revealed cell-type-specific dysregulation of the hub gene LIPA, which was upregulated in monocytes but downregulated in macrophages within the tumor microenvironment. Functional assays demonstrated that LIPA overexpression inhibited tumor proliferation in vitro and suppressed orthotopic tumor growth in vivo, at least in part through a ferroptosis-dependent mechanism involving TXNIP and ALOX5. Virtual screening further identified Castanospermine as a potential LIPA activator; treatment elevated LIPA expression, modulated the CD4+/CD8 + T-cell ratio, and attenuated tumor progression in mice. Collectively, these findings establish LIPA as a critical link between lipid metabolism, ferroptosis, and immune modulation in LUAD, and provide a prognostic signature for risk stratification as well as a candidate compound for targeting lipid metabolic vulnerabilities.

Keywords: Ferroptosis; LIPA; Lipid metabolism; Lung adenocarcinoma; Single-cell analysis

DOI: https://doi.org/10.1007/s11010-026-05741-5

J Cell Commun Signal. 2026 Sep;20(3): e70115

NRF2-CDH6-CEBPD axis suppresses ferroptosis and drives cisplatin resistance in non-small cell lung cancer.

Guang-Ze Zhou, Zhuo-Hang Zhu, Hong-Li Liao, Rui-Heng Chen, Dan-Ni Wu, Ri-Sheng Huang.

Ferroptosis is a non-apoptotic form of programmed cell death driven by iron-dependent lipid peroxidation. Induction of ferroptosis has been shown to overcome chemoresistance in cancer cells. Given the importance of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway in the regulation of cellular oxidative stress, this study was designed to search for NRF2-regulated genes involved in ferroptosis and chemoresistance in non-small cell lung cancer (NSCLC). Bioinformatics analysis and experimental validation indicated cadherin-6 (CDH6) as a candidate gene. The expression and role of CDH6 in NSCLC were explored. CDH6 protein partners were identified and investigated after CDH6 co-immunoprecipitation assays and mass spectrometry. Our data demonstrated that NRF2 binding to the promoter of the CDH6 gene inhibited RUNX2-mediated transcription of CDH6 in NSCLC. Clinically, CDH6 was downregulated in NSCLC tissues and correlated with more advanced tumor-node-metastasis (TNM) stage and shorter overall survival. Knockdown of CDH6 enhanced the proliferation, colony formation, tumorigenesis, and cisplatin (CDDP) resistance in NSCLC cells. Moreover, overexpression of CDH6 induced ferroptosis and increased CDDP sensitivity in CDDP-resistant NSCLC cells. Mechanistically, CDH6 associated with and sequestered CCAAT enhancer binding protein delta (CEBPD) protein in the cytoplasm and impaired the CEBPD-dependent transcription of target genes. Depletion of CEBPD increased CDDP sensitivity of CDH6-depleted NSCLC cells, whereas overexpression of CEBPD restored CDDP resistance in CDH6-overexpressing NSCLC cells. Additionally, CEBPD upregulation was associated with poor prognosis in NSCLC patients. In conclusion, our data underscore the critical role of the NRF2-CDH6-CEBPD axis in modulating CDDP sensitivity in NSCLC and offer a potential therapeutic target for improving chemotherapy.

Keywords: CDH6; chemotherapy; drug resistance; ferroptosis; lung cancer

DOI: https://doi.org/10.1002/ccs3.70115

Cancer Treat Res Commun. 2026 Sep 21. pii: S2468-2942(26)00356-4. [Epub ahead of print]49 101446

Identification of biomarkers associated with enhanced survival in lung cancer patients undergoing immune checkpoint inhibitor treatment.

Ilse Visser, Erick Suazo-Zepeda, T Jeroen N Hiltermann, Marjolein A Heuvelmans, Hylke C Donker, Willemijn J Maas, Geertruida H de Bock.

INTRODUCTION: Immunotherapy has revolutionized lung cancer treatment but has a relatively low response rate. Identification of predictive biomarkers could potentially identify patients for whom response can be expected. In this study, we aim to identify biomarkers from routine lab samples associated with better progression-free survival (PFS) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC), receiving immune checkpoint inhibitors (ICIs).
METHODS: Patients aged ≥18 with advanced stage (III and IV) lung cancer, treated with ICIs and who signed the OncoLifeS data-biobank informed consent were included. We conducted univariate and multivariable Cox-regression analyses to identify blood-based biomarkers associated with PFS and OS (adjusted for PD-L1 expression, ECOG performance status, cancer stage, treatment line, type of treatment, histological type, age, body mass index, smoking status and sex).
RESULTS: In total, 411 patients were included. Median PFS was 4.8 (interquartile range [IQR]: 1.49-16.67) months, and the median OS was 11.0 (IQR: 4.44-24.61) months. After Holm-Bonferroni correction, multivariable Cox-regression identified a decrease of neutrophil lymphocyte ratio (NLR), neutrophil count, lactate dehydrogenase (LDH), gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), c-reactive protein (CRP) and an increase in albumin to be significantly associated with lowered risk of progression and death. A decrease in cortisol and increase in creatinine was significantly associated with improved survival, but not PFS.
CONCLUSION: These findings suggest that biomarkers reflecting reduced inflammation, absence of metastasis and potentially improved nutritional status may be associated with improved PFS and OS in patients with advanced NSCLC receiving ICIs.

Keywords: Biomarkers; Immune checkpoint inhibitors; Immunotherapy; Lung cancer; Non-small cell lung cancer

DOI: https://doi.org/10.1016/j.ctarc.2026.101446

Cell Rep. 2026 Sep 23. pii: S2211-1247(26)01130-7. [Epub ahead of print]45(10): 118052

Dietary α-ketoglutarate modulates lung adenocarcinoma growth and epigenetic remodeling in a sex-dependent fashion.

Martín Alcaraz, Aparamita Pandey, Mia Santiago, Camelia Dumitras, Leilani Pradis, Estefany Gomez, Adriana Soto, Pasquale Saggese, Abigail S Krall, Bin Liu, Heather R Christofk, Steven M Dubinett, Xue Li, Claudio Scafoglio.

Lung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer-related mortality, underscoring the need for new chemopreventive strategies. α-Ketoglutarate (αKG), a tricarboxylic acid cycle metabolite and dioxygenase cofactor, links cellular metabolism to chromatin regulation. Here, we demonstrate that dietary calcium αKG (Ca-αKG) is associated with remodeling of LUAD in a sex-dependent manner. In female mice, Ca-αKG is associated with reduced tumor area, decreased repressive histone marks (H3K27me3 and H3K9me3), and upregulated TBX5 and myogenesis-associated genes. In male mice, Ca-αKG is associated with increased tumor area and elevated H3K27me3. Analysis of human LUAD revealed that TBX5 expression is enriched in female tumors and associated with improved survival, suggesting it may serve as a marker of favorable outcome. Together, these findings support Ca-αKG as an epigenetic modulator with potential chemopreventive activity in lung cancer and highlight the importance of incorporating sex as a biological variable in preclinical studies.

Keywords: CP: cancer; Tbx5; chemoprevention; dietary supplement; differentiation; epigenetics; histone methylation; lung cancer; metabolism; sexual dimorphism; α-ketoglutarate

DOI: https://doi.org/10.1016/j.celrep.2026.118052

J Immunother Cancer. 2026 Sep 25. pii: e016077. [Epub ahead of print]14(9):

METLUNG: plasma metabolomic profiling identifies metabolomic signatures associated with immunotherapy outcomes in non-small cell lung cancer.

Clara Lucía-Gozálvez, Christopher Papandreou, Joan Badia, Raquel Cumeras, Sergio Peralta, Cristina Martí, Ana Vidaller, Laura Quintana, Salvador Martínez, Josep Gumà.

BACKGROUND: Identifying reproducible biomarkers associated with treatment outcomes remains a major unmet clinical need in advanced non-small cell lung cancer (NSCLC). METLUNG evaluated whether plasma metabolomic profiling, alone or combined with clinical variables, could identify biomarkers associated with clinical response and survival outcomes in patients with NSCLC treated with immune checkpoint inhibitors.
METHODS: METLUNG is a prospective observational cohort (ISRCTN98848959) that enrolled 128 patients with stage III-IV NSCLC eligible for immune checkpoint inhibitors between October 2020 and December 2022 at Hospital Universitari Sant Joan de Reus, Reus (Spain). Clinical response classification was based on Immune Response Evaluation Criteria in Solid Tumors criteria, and subsequent clinical and radiological course. Baseline plasma metabolomic profiling was followed by univariate analyses and multivariate modeling. Survival models were built using clinical variables, metabolomic variables, significant metabolites, and an integrated clinical-metabolomic composite model. Predictive performance was evaluated using integrated area under the receiver operating characteristic curve and concordance index (C-index).
RESULTS: Among 127 evaluable patients, 52.8% achieved a clinical response. Most had adenocarcinoma (n=94), followed by squamous carcinoma (n=28). Treatment included first-line immunotherapy monotherapy (n=39), first-line chemo-immunotherapy (n=47), or second-line immunotherapy (n=41). Clinical response differed by sex and Eastern Cooperative Oncology Group performance status but showed no association with smoking history or PD-L1 expression.Univariate analyses identified 41 baseline metabolites associated with response, and 69 and 71 metabolites associated with progression-free survival and overall survival (OS), respectively. Five metabolites (histidine, citric acid, uracil, lactic acid, and sarcosine) remained consistently significant across all endpoints. Higher histidine and citric acid levels were associated with improved outcomes, whereas uracil, lactic acid, and sarcosine correlated with worse outcomes. The integrated clinical-metabolomic model showed the highest prognostic performance compared with clinical or metabolomic prognostic models alone, providing better early survival discrimination. In the immunotherapy monotherapy subgroup, only the integrated model was significant for OS, while metabolomic signatures showed stronger prognostic value.
CONCLUSIONS: Metabolomic profiling identified metabolic signatures associated with clinical response and survival outcomes in NSCLC patients treated with immune checkpoint inhibitors. An integrated clinical-metabolomic model showed improved prognostic stratification, supporting the potential value of plasma metabolomics for patient risk stratification. These findings remain exploratory and require validation in independent, ideally multicenter, cohorts before clinical implementation.
TRIAL REGISTRATION NUMBER: ISRCTN98848959.

Keywords: Biomarker; Immunotherapy; Lung Cancer

DOI: https://doi.org/10.1136/jitc-2026-016077

Front Immunol. 2026 ;17 1861545

Circulating cytokines as potential dynamic biomarkers of PD-1 blockade response and prognosis in non-small cell lung cancer.

Bo Peng, Yongyuan Li, Shuyuan Li, Jiajun Pan, Weimin Qian, Qingpeng Li.

Programmed death 1 (PD-1) inhibitors have transformed the treatment of advanced non-small cell lung cancer (NSCLC), but durable responses remain limited to a subset of patients. Conventional biomarkers, including PD-L1 expression and tumor mutational burden, are constrained by tissue accessibility, intratumoral heterogeneity, and limited capacity for dynamic monitoring. Circulating cytokines offer a minimally invasive alternative because they reflect systemic inflammation, antitumor immunity, and treatment-related immune activation. Evidence indicates that serum levels and on-treatment changes in TNF-α, IFN-γ, IL-6, IL-8, IL-17A, IL-1β, IL-2, IL-5, and IL-10 are associated with response, survival, and immune-related adverse events during PD-1 blockade. In general, declines in IL-6, IL-8, IL-17A, and IL-10, together with transient increases in IFN-γ and TNF-α, may indicate favorable immune reinvigoration, although findings remain inconsistent across studies. This review summarizes the biological functions, mechanistic roles, and clinical relevance of circulating cytokines as dynamic biomarkers, evaluates their potential values and current limitations in predicting the efficacy of PD-1 inhibitor therapy in NSCLC.

Keywords: PD-1 blockade; immune response; non-small cell lung cancer; predictive marker; prognosis; serum cytokines

DOI: https://doi.org/10.3389/fimmu.2026.1861545