bims-meluca 2026-06-28 papers

Cytotechnology. 2026 Aug;78(4): 138

Differential effects of thymoquinone under low-glucose stress in LKB1-null A549 and LKB1-wild-type H1299 lung cancer cells.

Betül Yılmaz Öztürk, Bükay Yenice Gürsu, İlknur Dağ, Onur Koyuncu.

Lung cancer remains one of the leading causes of cancer-related deaths worldwide, and the effects of thymoquinone on lung cancer cells have been increasingly investigated in recent years. Rapidly proliferating cancer cells exhibit increased metabolic activity and energy requirements, and the Liver Kinase B1 (LKB1) plays a crucial role in metabolic adaptation. In this study, the effects of thymoquinone on LKB1-null (A549) and LKB1-wild-type (H1299) lung cancer cell lines were investigated under high and low glucose stress conditions. Under high glucose conditions, thymoquinone showed a dose- and time-dependent cytotoxic effect in H1299 cells, with a 24-hour IC₅₀ value of 23.4 µM. In A549 cells, a hormetic response was observed at low and moderate doses, cytotoxicity occurred only at high doses, and the 24-hour IC50 value was determined as 69.45 µM. Under low glucose conditions, the cytotoxic effect of thymoquinone was increased in both cell lines; 24-hour IC₅₀ values were determined as 15 µM for H1299 and 16 µM for A549 cells. Overall, H1299 cells were found to be more sensitive to thymoquinone, especially at lower doses and earlier time points. Thymoquinone and glucose levels affected autophagy differently depending on the cell line. In H1299 cells, low glucose and thymoquinone administration significantly increased autophagy, while in A549 cells, both low glocose stress and thymoquinone suppressed autophagy. In contrast, thymoquinone increased apoptosis in both cell lines; this increase was particularly pronounced in late-stage apoptosis and was observed at much higher rates in A549 cells. However, LKB1 status alone may not be sufficient to determine the metabolic stress response, and additional molecular factors such as p53 protein may play a role in this process. A possible mechanistic explanation for this observed difference could be that H1299 cells are TP53-null, whereas A549 cells are harbor wild-type TP53. Our findings suggest that the effects of thymoquinone may vary depending on the cellular genetic background and are shaped by multidimensional mechanisms under conditions of metabolic stress, and detailed studies on this subject are needed.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-026-01009-4.

Keywords: A549; Apoptosis; Autophagy; H1299; LKB1; Metabolic stress; Thymoquinone

DOI: https://doi.org/10.1007/s10616-026-01009-4

Discov Oncol. 2026 Jun 23.

Metabolic pathway signatures define prognostic subtypes of lung adenocarcinoma.

Doris Kafita, Zitha Mukwamba, Vanity Mapulanga, Adon Chawe, Musalula Sinkala.

Metabolic reprogramming is a core hallmark of cancer, yet how it contributes to the clinical heterogeneity of lung adenocarcinoma (LUAD) remains poorly understood. Here, by applying unsupervised clustering to the metabolic transcriptomes of 510 LUAD tumours, we identify two robust and prognostically significant subtypes. We show that these subtypes have divergent clinical outcomes, with subtype-1 patients exhibiting significantly longer overall and disease-specific survival compared to the more aggressive subtype-2. This clinical distinction is underpinned by fundamentally different metabolic architectures: the aggressive subtype-2 is characterized by the upregulation of central carbon metabolism, including the citric acid cycle and respiratory electron transport, whereas the less aggressive subtype-1 shows a distinct enrichment for choline catabolism. Consistent with this, Cox regression analysis reveals that high expression of the TCA cycle enzyme OGDH is a top predictor of increased disease risk, while the glycolytic enzyme PGK1 is associated with a decreased risk. Our findings establish a direct link between transcriptional metabolic states and patient survival in LUAD, defining a framework for prognostic stratification and identifying subtype-specific metabolic vulnerabilities for therapeutic targeting.

Keywords: Bioinformatics; Choline metabolism; Citric acid cycle; Lung adenocarcinoma; Machine learning; Metabolic reprogramming; Prognosis; Survival analysis; Transcriptome; Tumour subtyping

DOI: https://doi.org/10.1007/s12672-026-05480-5

bioRxiv. 2026 Jun 08. pii: 2026.06.03.729911. [Epub ahead of print]

SMARCA4, STK11, and KEAP1 co-inactivation associates with poor prognosis and upregulation of the TGF-β pathway in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is clinically and molecularly defined by oncogenic driver mutations, identification of which has led to the development of driver-targeted therapies and substantial improvements in prognosis for subsets of LUAD patients. Recent studies assessing clinical outcomes in the context of multigenic alterations have identified secondary mutations that might explain differential responses to targeted therapies, chemotherapies and immunotherapies. Genetic inactivation or loss of SMARCA4 , which frequently co-occurs with loss-of-function mutations in STK11 and KEAP1 , is especially predictive of poor prognosis and shorter overall survival in LUAD patients, regardless of driver status. We sought to examine the clinical and functional associations of SMARCA4 deficiency in LUAD, with or without co-associated STK11/KEAP1 loss-of-function.
Methods: We examined correlation between SMARCA4 loss, gene expression and prognosis through genomic and transcriptomic profiling of clinically annotated LUAD samples. We generated isogenic cell line models with genetic knockouts of SMARCA4 with or without concomitant STK11 and KEAP1 to profile mutationally-defined genotypes of interest in vitro and in vivo . Lastly, we interrogated the functional dependency of SMARCA4/STK11/KEAP1 triple mutant models on TGF-β signaling to assess its potential as a therapeutic target.
Results: SMARCA4/STK11/KEAP1 triple mutant LUAD is associated with poor survival and high frequency of multisite metastasis. SMARCA4/STK11/KEAP1 triple knockout models showed enhanced migration and invasion in vitro , and diversified organotropism in an in vivo intracardiac xenograft metastasis assay. RNA-Seq and DNaseI-Seq of these in vitro models and clinical samples identified upregulation of TGF-β signaling and EMT gene expression signatures, and corresponding changes in chromatin accessibility, in SMARCA4/STK11/KEAP1 triple mutant LUAD.
Conclusions: We identify SMARCA4/STK11/KEAP1 triple mutant LUAD as a prognostically significant disease subset and nominate TGF-β signaling as a potential therapeutic target.

DOI: https://doi.org/10.64898/2026.06.03.729911

Biomedicines. 2026 Jun 01. pii: 1262. [Epub ahead of print]14(6):

ZIP7 Drives Glycolytic Reprogramming and Lactate-Mediated Immune Remodeling in Lung Adenocarcinoma Through GSK3β-NRF2 Signaling.

Zhihua Tang, Yueli Shi, Xinyuan Jiang, Sujing Jiang, Nueraili Maihemuti, Jie Zhang, Bufu Tang, Zhiyong Xu.

Background: Zinc homeostasis regulated by ZIP transporters is critical for tumor glycolytic reprogramming and progression, yet the role of specific ZIP family members in lung adenocarcinoma (LUAD) remains unclear. This study aimed to identify the key ZIP transporter in LUAD and elucidate its molecular mechanisms and therapeutic value. Methods: siRNA-based functional screening of the ZIP family was performed in A549 and PC9 cells. A combination of in vitro cellular assays, in vivo animal models, clinical sample analysis and bioinformatics was used to validate the function of ZIP7 and explore its regulatory mechanisms. Results: ZIP7 (SLC39A7) was identified as a critical driver of glycolysis and proliferation in LUAD. It was significantly upregulated in LUAD tissues and cell lines. Mechanistically, ZIP7 increased inhibitory phosphorylation of GSK3β at Ser9 to stabilize NRF2, maintained low intracellular ROS levels, and sustained mTOR signaling to promote glycolytic flux. ZIP7-induced lactate secretion also drove M2-like macrophage polarization and PD-L1 upregulation to establish an immunosuppressive microenvironment. Notably, genetic or pharmacological inhibition of ZIP7 markedly enhanced the antitumor efficacy of anti-PD-1 therapy in vivo. Conclusions: ZIP7 is a pivotal oncogenic zinc transporter in LUAD that drives tumor progression via metabolic reprogramming and immune remodeling. Targeting ZIP7 represents a promising strategy to improve the efficacy of anti-PD-1 immunotherapy for LUAD.

Keywords: NRF2; ZIP7; anti-PD-1 therapy; glycolysis; lung adenocarcinoma; tumor-associated macrophages

DOI: https://doi.org/10.3390/biomedicines14061262