bims-meluca 2026-02-01 papers

Front Endocrinol (Lausanne). 2025 ;16 1630503

Impact of pre-therapeutic fasting plasma glucose on survival outcomes in advanced non-small cell lung cancer patients.

Feiwen Liu, Min Luo, Fang Wang, Ting Liang, Xiaochen Wang.

Purpose: The necessity of tight glycemic management in non-small cell lung cancer (NSCLC) remains controversial. This study aimed to determine whether baseline fasting plasma glucose (FPG) levels could serve as an independent prognostic marker for survival outcomes in advanced NSCLC.
Patients and methods: This study included 960 patients with advanced NSCLC, who were categorized into low (< 3.9 mmol/L), normal (3.9-6.1 mmol/L), and high FPG groups (> 6.1 mmol/L) based on pre-treatment FPG levels. The analyzed covariates included demographics, clinical characteristics, oncogenic mutation status, and first-line treatments. Survival curves with log-rank tests were estimated to compare survival differences between groups. Univariate and multivariate Cox proportional hazards regression were performed to investigate the prognostic factors. Furthermore, smooth curve fitting and piecewise Cox regression were used to explore the non-linear relationships between FPG and mortality risk, while subgroup analyses were employed to test interactions.
Results: Both low (12.0 vs. 18.5 months, P = 0.0093) and high (14.4 vs. 18.5 months, P = 0.0049) FPG levels were significantly associated with shorter median survival times compared to normal FPG levels. Multivariable analyses further identified low FPG (HR 1.41, 95% CI 1.06-1.88; P = 0.0196) and high FPG (HR 1.43, 95% CI 1.11-1.85; P = 0.0059) as independent prognostic risk factors. Smooth curve fitting and piecewise Cox proportional hazards models revealed a negative linear relationship between FPG levels and mortality risk (HR 0.70, 95% CI 0.52-0.94; P = 0.0185) when FPG was below the breakpoint of 4.46 mmol/L, and a positive linear relationship (HR 1.11, 95% CI 1.04-1.19; P = 0.0015) when FPG exceeded the breakpoint. Subgroup analyses consistently supported these findings across all patient subgroups, with no specific population exhibiting distinct outcomes.
Conclusion: Abnormal FPG levels are independent risk factors for the long-term prognosis of advanced NSCLC. Further prospective multicenter studies are needed to confirm these associations and clarify whether glycemic assessment and management influence survival outcomes.

Keywords: fasting plasma glucose (FPG); glycemic management; non-small cell lung cancer (NSCLC); prognostic biomarker; smooth curve fitting

DOI: https://doi.org/10.3389/fendo.2025.1630503

J Extracell Vesicles. 2026 Jan;15(1): e70219

Profiling of Extracellular Vesicles of Non-Small Cell Lung Cancer Reveals Proteins Associated With Osimertinib Resistance.

Albano Cáceres-Verschae, Petra Hååg, Sofia Joelsson, Per Hydbring, Bo Franzén, Ákos Végvári, Inger Johanne Z Eide, Nupur Agarwal, Siddharth Sourabh Sahu, Fredrik Stridfeldt, Luigi De Petris, Apurba Dev, Simon Ekman, Odd Terje Brustugun, Rolf Lewensohn, Kristina Viktorsson.

Precision cancer medicine with small tyrosine kinase inhibitors (TKIs) directed toward oncogenic drivers, are important treatment regimens for solid tumours. The epidermal growth factor receptor (EGFR)-TKI osimertinib is a preferred therapy for patients with non-small cell lung cancer (NSCLC) driven by activating mutations in EGFR, unfortunately responses are heterogeneous. This calls for non-invasive methods to predict or monitor treatment response, for example, via biomarker analyses in blood. To reveal such putative biomarkers, we analysed the proteome of extracellular vesicles (EVs) from osimertinib resistant or responsive NSCLC cells in vitro and from EVs isolated from serum samples of NSCLC patients treated with osimertinib in second line within the phase II clinical trial TREM. The protein cargo of the EVs was analysed by mass spectrometry (MS) and proximity extension assay (PEA). Western blotting, ELISA and single vesicle analysis was performed to validate and further confirm the expression of certain proteins. MS profiling of the NSCLC cells and their released EVs revealed a protein signature associated with osimertinib refractoriness. Among them were CSPG4, HSPG2, MCAM, L1CAM, TAGLN, THBS1 and TNC. GO-pathway analysis related several of these proteins to the focal adhesion and proteoglycan in cancer pathways. Some of these proteins, including CSPG4, which when suppressed by transient siRNA transfection in NSCLC cells resulted in reduced cell viability, were expressed also in EVs from serum of the NSCLC patients. Moreover, PEA profiling of the serum-isolated EVs revealed signatures associated with immune cells, best response and/or progression-free survival, including PD-L1, CD73/NT5E, FR-alpha/FOLR1, LAMP3, FASLG1 and ANXA1. In summary, we demonstrate that protein profiling of EVs in relation to osimertinib refractoriness has the potential to identify possible biomarkers that can indicate osimertinib treatment resistance, for example, CSPG4, HSPG2, TAGLN, TNC, THBS1, ANXA1 and CD73/NT5E. Studies in expanded cohorts should be conducted to further validate these putative osimertinib biomarkers.

Keywords: biomarkers; extracellular vesicles; mutant epidermal growth factor receptor; non‐small cell lung cancer; osimertinib

DOI: https://doi.org/10.1002/jev2.70219

Front Nutr. 2025 ;12 1706391

The impact of cachexia index combined with BMI trajectory on survival outcomes in patients with cancer cachexia.

Xue Cheng, Lijuan Guo, Junhao Ren, Jiaying Mo, Qing Li, Xin Jin, Yong Liu.

Background: The cachexia index (CXI) has emerged as a recognized prognostic biomarker of cancer cachexia. However, the dynamic progression of cachexia may not be fully captured by a single assessment. This study examined the impact of integrating the CXI with BMI trajectories on the survival prognosis of patients with cancer cachexia to enable early identification of high-risk populations.
Methods: This is a retrospective review of clinical and pathological data from 147 patients diagnosed with cancer cachexia at Xuzhou Central Hospital between January 2019 and May 2024. Based on computed tomography images at the time of initial cancer cachexia diagnosis to calculate the L3-SMI, the CXI was calculated using serum albumin (ALB) level, neutrophil-to-lymphocyte ratio (NLR), and skeletal muscle index (SMI). Using X-tile software, gender-specific optimal cutoff values for CXI were determined, and patients were divided into low and high CXI groups. Multiple BMI measurements were collected, and BMI dynamic trajectory subtypes were identified using latent category growth mixture modeling (GMM). Cox regression analysis was performed to identify independent risk factors for overall survival (OS); Kaplan-Meier survival curves were plotted; and subgroup interactions were analyzed according to cancer type, BMI trajectory subtype, ECOG PS, and TNM stage. A heterogeneity analysis of CT-based body composition was conducted to evaluate the relationship between muscle and adipose tissue.
Results: GMM revealed two types of BMI decline trajectories: Class 1 (low reserve-slow decline BMI, 58%) and Class 2 (high reserve-accelerated decline BMI, 42%). The low CXI group had a considerably shorter median OS compared to the high CXI group (4.5 vs. 8.3 months, p < 0.001), with the low CXI and Class 1 subgroup having the poorest prognosis (median OS 3.5 months vs. other subgroups, p < 0.001). Multivariate Cox regression analysis identified low CXI, ECOG PS 2-3, and TNM Stage III-IV as independent risk factors for OS (p < 0.05). Subgroup analysis showed that low CXI significantly increased the risk of death in patients with gastrointestinal cancer, Class 1, and TNM Stage III-IV (p < 0.05), and there was no interaction with cancer type, BMI trajectory subtype, ECOG PS, or TNM Stage (p > 0.05). The third lumbar spinal muscle area (L3-SMA) was weakly positively correlated with subcutaneous fat thickness (SFT) (Spearman r = 0.256, p = 0.0018).
Conclusion: The combination of low CXI and Class 1 trajectory was identified as an exceedingly high-risk phenotype with markedly poor survival, mandating early intensive intervention. This novel composite model provides a critical foundation for early risk stratification and precise intervention strategies in cancer cachexia, with the potential to significantly improve patient prognosis.

Keywords: BMI trajectory; cachexia index; cancer cachexia; risk stratification; subcutaneous fat thickness; survival prognosis

DOI: https://doi.org/10.3389/fnut.2025.1706391

Transl Oncol. 2026 Jan 24. pii: S1936-5233(26)00022-7. [Epub ahead of print]65 102685

Ferroptosis induction enhances anti-PD-1 efficacy in NSCLC via HIF-1α/PD-L1 modulation.

Zimin Wang, Hao Liu, Jiawei Liang, Ying Zhang, William C Cho, Minhua Ye, Dehua Ma, Min Kong, Chengchu Zhu, Jianfei Shen.

BACKGROUND: The monotherapeutic efficacy of immune checkpoint inhibitors (ICIs) remains unsatisfactory in patients suffering from non-small-cell lung cancer (NSCLC). Ferroptosis, an iron-dependent cell death process, has been identified as a promising immunotherapy adjuvant; however, ferroptosis inducers (such as erastin, RSL3) may paradoxically up-regulate hypoxia-inducible factor 1α (HIF-1α) and programmed death ligand 1 (PD-L1) to propel tumor immune evasion. It is critical to explore the molecular mechanism of ferroptosis in NSCLC immunotherapy and verify the efficacy of combined regimens for overcoming ICI limitations clinically.
METHODS: This work analyzed 162 NSCLC patients receiving immunotherapy retrospectively to evaluate correlation between PD-L1 expression and progression-free survival (PFS). In vitro, CCK-8 assay, flow cytometry, qPCR, and Western blotting were utilized to measure impacts of ferroptosis inducers (Erastin, RSL3) upon cell viability, reactive oxygen species (ROS) levels, and PD-L1/HIF-1α expression in A549/H1299 NSCLC cells; ferroptosis-specific effects were validated by means of iron chelators (DFO, ferrostatin-1). In vivo, subcutaneous tumor models were built in C57BL/6 mice with LLC cells; therapeutic effects of ferroptosis inducer (IKE) alone or combined with anti-PD-1 antibody were evaluated through tumor weight measurement and immunohistochemistry (IHC). HIF-1α binding to PD-L1 promoter was confirmed via chromatin immunoprecipitation (ChIP); related signaling pathways were explored using transcriptome sequencing and KEGG enrichment analysis.
RESULTS: For NSCLC patients who received immunotherapy, high PD-L1 expression correlated with longer PFS, and 4-HNE was associated positively with PD-L1 and CD8⁺T infiltration. In vitro, Erastin/RSL3 induced dose-dependent cell death, ROS accumulation, and PD-L1 up-regulation, reversed by iron chelators. In vivo, IKE+anti-PD-1 inhibited tumor growth significantly, whereas it increased CD8⁺T infiltration. Mechanistically, Erastin up-regulated HIF-1α via PI3K-AKT, which bound PD-L1 promoter (ChIP-verified), reversed by iron chelators.
CONCLUSIONS: Ferroptosis inducers have dual effects in NSCLC, namely, promoting tumor cell death and triggering PD-L1-dependent immune evasion via the PI3K-AKT-HIF-1α pathway. However, combining ferroptosis inducers with anti-PD-1 antibodies retains the anti-tumor effect of ferroptosis and overcomes immune evasion by obstructing the PD-L1 pathway, offering a novel strategy for enhancing NSCLC immunotherapy efficacy.

Keywords: Ferroptosis; HIF-1α; Non-small-cell lung cancer; PD-l1; Tumor immune microenvironment

DOI: https://doi.org/10.1016/j.tranon.2026.102685

Biochem Pharmacol. 2026 Jan 22. pii: S0006-2952(26)00077-8. [Epub ahead of print] 117746

TRAF6 promotes the ferroptosis defense through AKT/mitochondria damage in KRAS-driven lung cancer.

Weibang Yu, Yiwen Cui, Sixin Li, Lianxiang Luo.

Ferroptosis, an iron-dependent form of cell death, has emerged as a therapeutic vulnerability in cancer, yet its regulation in kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung cancer remains poorly defined. Here we identified tumor necrosis factor receptor-associated factor 6 (TRAF6) as a critical driver of mitochondria-dependent ferroptosis in KRAS-driven lung cancer. TRAF6 inhibition increased lipid peroxidation, mitochondrial reactive oxygen species (ROS), and Fe2+ accumulation, thereby exacerbating mitochondrial damage and enhancing RAS-selective lethal 3 (RSL3)-induced ferroptosis. Genetic silencing of TRAF6 impaired anti-oxidative signaling and markedly suppressed KRAS-mutant lung cancer growth in vivo. Mechanistically, TRAF6 directly interacted with protein kinase B (AKT) to induce the mitochondrion damage and ferroptosis, which was reversed by AKT overexpression or the mitochondrial antioxidant treatment. Through virtual screening, a novel TRAF6-targeted inhibitor pentagalloylglucose (PGG) was identified. PGG bind and degraded TRAF6 efficiently, triggering mitochondrial ferroptosis and robustly suppressing the growth of KRAS-mutant lung cancer, with partial rescue by ferroptosis blockade. These findings uncovered a previously unrecognized TRAF6/AKT-mediated mitochondrial ferroptosis axis and highlighted PGG as a promising candidate against KRAS-mutant lung cancer.

Keywords: Ferroptosis; KRAS; Lung cancer; Mitochondria; Pentagalloylglucose (PGG); TRAF6

DOI: https://doi.org/10.1016/j.bcp.2026.117746