bims-meluca 2026-05-03 papers

Curr Issues Mol Biol. 2026 Apr 14. pii: 403. [Epub ahead of print]48(4):

TRIM24 Regulates Adaptation to Glucose Deprivation in Association with Aspartate Accumulation and Impaired AMPK Signaling.

Xiaochen Yu, Duopeng An, Dadui Ren, Peng He, Yunkai Yang, Nanye Chen, Rui Wang, Shan Wu, Jun Feng, Meiqing Feng.

Glucose deprivation is a major metabolic stress that requires coordinated adaptive responses to maintain cellular homeostasis and survival, yet the role of tripartite motif-containing 24 (TRIM24) in this process remains unclear. To address this question, we generated CRISPR-Cas9-mediated TRIM24-knockout MCF-7 and HEK293 cell lines, performed targeted metabolomic profiling and aspartate assays, used 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), aminooxyacetic acid (AOA), aspartate supplementation, and glutamic-oxaloacetic transaminase 2 (GOT2) knockdown to probe AMPK signaling and aspartate metabolism, and examined starvation responses in constitutive Trim24 knockout mice on a C57BL/6 background. Loss of TRIM24 sensitized cells to glucose deprivation. Re-expression of TRIM24 partially restored cell viability under glucose deprivation in both MCF-7 and HEK293 cells. Under glucose-free conditions, TRIM24 deficiency was associated with impaired AMP-activated protein kinase (AMPK) pathway activation, increased intracellular aspartate accumulation, and altered ATP/AMP levels. Pharmacological reactivation of AMPK by AICAR improved the survival of TRIM24-deficient cells under glucose deprivation. Reducing intracellular aspartate by AOA treatment or GOT2 knockdown restored AMPK pathway activation and improved adaptation to glucose deprivation, whereas exogenous aspartate suppressed AMPK signaling and increased ATP/AMP levels. In vivo, starvation of Trim24-deficient mice was associated with reduced AMPK pathway activation and increased aspartate levels. Together, these findings support a model in which TRIM24 contributes to adaptation to glucose deprivation and in which abnormal aspartate accumulation contributes to impaired AMPK pathway activation in TRIM24-deficient cells.

Keywords: AMPK signaling; TRIM24; aspartate metabolism; glucose deprivation; metabolic adaptation; nutrient stress

DOI: https://doi.org/10.3390/cimb48040403

Anticancer Res. 2026 May;46(5): 2789-2806

Cancer Cachexia Predicts Benefit of Immunotherapy Plus Chemotherapy in EGFR-mutant NSCLC After TKI Resistance.

BACKGROUND/AIM: Cancer cachexia, characterized by weight loss and systemic inflammation, has been associated with poor prognosis in non-small cell lung cancer (NSCLC). However, its impact on treatment outcomes in tumors with mutant epidermal growth factor receptor (EGFR) remains unclear. This multicenter retrospective cohort study evaluated the impact of cancer cachexia on treatment selection after the development of resistance to EGFR tyrosine kinase inhibitors (TKIs).
PATIENTS AND METHODS: This study included 439 patients with advanced EGFR-mutant NSCLC who received chemotherapy (n=304) or immune checkpoint inhibitors (ICIs) combined with chemotherapy (n=135) after EGFR-TKI failure. Cancer cachexia was diagnosed based on specific weight loss criteria and laboratory data. Propensity score matching was performed to adjust for baseline differences, and survival outcomes were compared.
RESULTS: Overall, significant differences in treatment outcomes were observed between the groups. In the chemotherapy group, cancer cachexia was an independent predictor of overall survival (hazard ratio=1.53; p=0.004), whereas it was not associated with survival in the ICIs/chemotherapy group. Among patients with cachexia, overall survival was significantly longer with ICIs/chemotherapy than with chemotherapy alone (13.8 vs. 11.2 months; p=0.049).
CONCLUSION: Although no significant survival difference was found between chemotherapy and ICIs/chemotherapy in the overall population, ICIs/chemotherapy conferred a survival benefit to patients with cancer cachexia. These findings suggest that the presence of cachexia may serve as a potential biomarker for treatment selection in EGFR-TKI-resistant, EGFR-mutant NSCLC.

Keywords: Cancer cachexia; epidermal growth factor receptor-mutant non-small cell lung cancer; epidermal growth factor receptor-tyrosine kinase inhibitor resistance; immune checkpoint inhibitors

DOI: https://doi.org/10.21873/anticanres.18159

Oncol Lett. 2026 Jun;31(6): 254

METTL5 reprograms glycolytic metabolism and promotes non-small cell lung cancer progression by modifying PGAM1.

Yuchen Shan, Xiaoyu Duan, Kai Yuan, Ming Lou, Qiyong Wu, Zhaojia Gao.

N6-methyladenosine (m6A) RNA methylation is implicated in cancer metabolism; however, to the best of our knowledge, the role of methyltransferase 5 (METTL5) in non-small cell lung cancer (NSCLC) progression remains unclear. Reprogrammed glycolytic metabolism (Warburg effect) supports tumor growth and immune evasion; however, the regulatory mechanisms of this process require further investigation. We hypothesized that METTL5 drives NSCLC progression by regulating glycolytic metabolism through m6A modification of phosphoglycerate mutase 1 (PGAM1) mRNA. The present study aimed to elucidate the molecular mechanisms, functional impacts and clinical relevance of the METTL5/PGAM1 axis. Integrated analyses of NSCLC cohorts from The Cancer Genome Atlas database were performed, and in vitro models (A549 and PC9 cell lines) and molecular techniques, including methylation inhibition, RNA stability assays and metabolic flux measurements (Seahorse XFe96 analyzer), were used. Key interactions were validated through western blotting, reverse transcription-quantitative PCR and correlation analyses. METTL5 was significantly upregulated in NSCLC tissues and in A549, PC9 and H520 cell lines, and high METTL5 expression was associated with poor patient survival (P<0.05). Silencing of METTL5 suppressed NSCLC cell proliferation and migration, while overexpression promoted proliferation and migration. METTL5 directly targeted PGAM1 mRNA through m6A modification, and the expression levels of METTL5 and PGAM1 exhibited a statistically significant but moderate positive correlation (R=0.45; P=5.4×10-56). YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) is an m6A reader that recognizes and binds to methylated PGAM1 mRNA, enhancing its stability and expression. PGAM1 knockdown reduced glycolysis (decreased extracellular acidification rate) and increased oxidative phosphorylation (increased oxygen consumption rate). Notably, the positive correlation between PGAM1 and GLUT1 expression (R=0.6; P=4.12×10-183) supports the role of the METTL5/PGAM1 axis in regulating GLUT1, thereby influencing glycolytic flux. Rescue experiments demonstrated that PGAM1 overexpression reversed GLUT1 downregulation in METTL5-knockdown cells. Overall, METTL5 may drive NSCLC progression by reprogramming glycolytic metabolism through m6A modification of PGAM1 mRNA. The METTL5/PGAM1/GLUT1 axis represents a novel therapeutic target for NSCLC.

Keywords: N6-methyladenosine RNA methylation; Warburg effect; glucose transporter type 1; methyltransferase 5; non-small cell lung cancer; phosphoglycerate mutase 1

DOI: https://doi.org/10.3892/ol.2026.15609

Cancer Med. 2026 May;15(5): e71901

Ubiquitin-Specific Protease 45 Inhibits Lung Adenocarcinoma Ferroptosis by Regulating Ubiquitination and Stability of Glutathione Peroxidase 4.

Mingxiang Huang, Meilan Fang, Yao Wang, Shanshan Liu, Fengqin Li.

Lung adenocarcinoma is the most common subtype of lung cancer and the leading cause of cancer-related mortality worldwide. Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a promising therapeutic target for lung adenocarcinoma. However, the molecular mechanisms that control ferroptosis sensitivity remain unclear. In this study, we identified ubiquitin-specific protease 45 (USP45) as a critical suppressor of ferroptosis in lung adenocarcinoma cells. Systematic screening of ubiquitin-specific proteases revealed that USP45 robustly enhanced glutathione peroxidase 4 (GPX4) protein expression. Bioinformatics analysis indicates that USP45 is significantly upregulated in lung adenocarcinoma patient datasets from the GEO and TCGA databases. Immunohistochemical results from the HPA database further corroborate this finding. Concurrently, elevated USP45 expression in lung adenocarcinoma patients frequently portends an unfavorable prognosis. Functional assays showed that USP45 depletion sensitized lung adenocarcinoma cells to erastin-induced ferroptosis, leading to impaired viability, colony formation, survival, migration, and invasion, whereas USP45 overexpression conferred resistance to ferroptotic stress and rescued the malignant phenotypes. Mechanistically, USP45 interacts with GPX4 and removes its ubiquitin chains, thereby stabilizing the GPX4 protein. Overexpression of GPX4 rescued ferroptosis sensitivity in USP45-deficient lung adenocarcinoma cells, whereas GPX4 depletion abrogated the protective effect of USP45 overexpression, establishing GPX4 as a functional mediator of USP45 activity. Collectively, these findings reveal a previously unknown USP45-GPX4 axis that promotes ferroptosis resistance and tumor progression in lung adenocarcinoma.

Keywords: GPX4; USP45; ferroptosis; lung adenocarcinoma; ubiquitination

DOI: https://doi.org/10.1002/cam4.71901