bims-meluca 2025-10-05 papers

Biochem Biophys Res Commun. 2025 Sep 30. pii: S0006-291X(25)01443-3. [Epub ahead of print]786 152727

Targeting IL-6/STAT3 signaling to mitigate sarcopenia: Insights from immuno-metabolic crosstalk in NSCLC.

Gautam Kumar, Shweta Khandibharad, Shailza Singh.

Non-small cell lung cancer (NSCLC) is the most prevalent subtype of lung cancer and a leading cause of cancer-related mortality worldwide. Literature evidences indicates a strong association between systemic inflammation, driven by cytokines such as Interleukin-6 (IL-6), and the development of NSCLC-associated sarcopenia. However, the immuno-metabolic underpinnings that link tumor-derived IL-6 signaling to skeletal muscle degradation remain incompletely understood. We developed a comprehensive immuno-metabolic mathematical model to investigate how IL-6 signaling influences branched-chain amino acids (BCAA) metabolism and redox homeostasis in the context of NSCLC-induced sarcopenia by understanding two key causes of sarcopenia which are malnutrition and redox homeostasis. Our model proposes that IL-6 alters tumor metabolism by activating the STAT3 pathway. Elevated IL-6 impairs protein synthesis, proteolysis, and muscle atrophy by interfering with insulin signaling, inhibiting mTORC1 activation, and increasing oxidative stress. Additionally, it reveals a central role for IL-6-driven metabolic rewiring, particularly BCAA utilization and redox imbalance, in promoting NSCLC-induced sarcopenia. These findings underscore the dual impact of IL-6 on tumor progression and systemic muscle degradation, and provide a framework for evaluating therapeutic strategies that target IL-6/STAT3 signaling and amino acid metabolism via STAT3 and acetyl-CoA cross talk to mitigate NSCLC-induced sarcopenia.

Keywords: IL-6; Immunometabolism; Muscle degradation; NSCLC; Sarcopenia

DOI: https://doi.org/10.1016/j.bbrc.2025.152727

Clin Transl Med. 2025 Oct;15(10): e70490

Distinct molecular subtypes of KRASG12C-mutant lung adenocarcinoma: Insights into clinical outcomes, tumour microenvironments and therapeutic strategies.

Haitang Yang, Anshun Zhu, Yongliang Niu, Wenyan Ma, Ke Xu, Yunxuan Jia, Weijiao Xu, Baicheng Zhao, Enshuo Zhang, Jiaying Jia, Shunqing Liang, Patrick Dorn, Gang Liu, Ren-Wang Peng, Feng Yao.

BACKGROUND: KRASG12C is the most common KRAS mutation in lung adenocarcinoma (LUAD), yet clinical responses to KRASG12C-selective inhibitors (G12Ci) and immunotherapy remain variable.
METHODS: Transcriptomic analysis of KRASG12C-mutant LUAD was performed using machine learning algorithms to classify molecular subtypes. Subtype-specific features, including genomic alterations, tumour microenvironment and therapeutic vulnerabilities, were systematically evaluated.
RESULTS: We identified three distinct molecular subtypes (KC1, KC2 and KC3) of KRASG12C-mutant LUAD through transcriptomic analysis using machine learning algorithms. KC1 subtype is characterised by a neuroendocrine phenotype associated with SMARCA4 loss-of-function and frequent STK11 co-mutations, with a relatively good prognosis. It exhibits poor immune infiltration and demonstrates resistance to G12Ci and immunotherapy but shows sensitivity to MEK1/2 inhibitors; KC2 subtype exhibits a highly malignant phenotype with high proliferation, increased glucose metabolism, and the poorest prognosis. It is enriched with T-cell infiltration and responds best to G12Ci monotherapy and immunotherapy. KC3 subtype is distinguished by well differentiation and the best survival, with an immune-enriched microenvironment featuring abundant immune-suppressive cancer-associated fibroblasts. It demonstrates limited sensitivity to G12Ci and a moderate response to immunotherapy. Notably, KC1‒3 subtype-specific molecular signatures predict drug sensitivity more accurately than classical KRASG12C signalling models.
CONCLUSIONS: These findings illuminate the intricate interplay between tumour subtypes, microenvironmental factors and therapeutic responses, offering a robust framework for improved patient stratification and the development of personalised therapeutic strategies KRASG12C-mutant LUAD.
KEY POINTS: Three novel molecular subtypes (KC1, KC2 and KC3) of KRASG12C-mutant lung adenocarcinoma were identified, each with distinct molecular and clinical characteristics. These subtypes demonstrate differential responses to both KRASG12C targeted therapy and immunotherapy, influencing treatment outcomes. This new classification system enables biomarker-guided combination therapies and informs future clinical trial design for these cancers.

Keywords: KRAS mutation; lung adenocarcinoma; molecular subtypes; precision oncology; treatment response; tumour immune microenvironment

DOI: https://doi.org/10.1002/ctm2.70490

Exp Cell Res. 2025 Sep 26. pii: S0014-4827(25)00376-3. [Epub ahead of print]452(2): 114776

Suppressor of Tumorigenicity 14 inhibits non-small cell lung cancer cell proliferation by suppressing Transketolase O-GlcNAcylation.

Lei Ji, Maowei Zhang, Yanan Liu, Hui Zhang, Tao Luo, Ling Zhao, Wenhui Zhang, Bi Chen, Rui Chen.

Suppressor of Tumorigenicity 14 Protein (ST14), a type II transmembrane serine protease, is a well-documented oncogenic driver in multiple malignancies. Paradoxically, its pathobiological functions in non-small cell lung cancer (NSCLC) remain incompletely defined. This study uncovers a previously unrecognized tumor-suppressive role for ST14: we demonstrate that ST14 overexpression significantly suppresses NSCLC cell proliferation in vitro and tumor growth in vivo. Mechanistically, we identify a novel ST14-Transketolase (TKT) regulatory axis, in which ST14 modulates cellular metabolism through post-translational modifications. Specifically, we establish the following: (i) TKT physically interacts with O-GlcNAc transferase (OGT) to undergo functional O-GlcNAcylation; (ii) ST14 competitively disrupts the TKT-OGT interaction, thereby ablating TKT O-GlcNAcylation; (iii) Such suppression of TKT glycosylation attenuates glycolytic flux, as evidenced by reduced glucose uptake and lactate production; (iv) The resulting metabolic impairment directly inhibits cellular proliferation. Collectively, these findings provide the first mechanistic evidence that ST14 constrains NSCLC cell proliferation via glycosylation-dependent metabolic reprogramming.

Keywords: Cell proliferation; NSCLC; O-GlcNAcylation; ST14; TKT

DOI: https://doi.org/10.1016/j.yexcr.2025.114776

Am J Epidemiol. 2025 Oct 01. pii: kwaf084. [Epub ahead of print]

Pre-diagnostic Body Mass Index Trajectories and Associations with Lung Cancer Risk.

Wen Zhou, Lorelei A Mucci, Mingyang Song, Hongbing Shen, Christopher I Amos.

Mendelian randomization can reveal the etiological association between body mass index (BMI) and lung cancer. However, the associations between the trajectories of BMI and the risk of lung cancer remain inconclusive. We employed growth mixture modeling to identify trajectories of pre-diagnostic BMI in 163,545 individuals (117,445 women from the Nurses' Health Study and 46,100 men from the Health Professionals Follow-Up Study). We assessed the associations between BMI trajectories and lung cancer risk, as well as the effects within subgroups. Four trajectories were identified: normal-moderate increasing (Class 1), overweight-marked increasing (Class 2), overweight-obese turning (Class 3), and obese-persistent (Class 4). We observed a decreased risk of lung cancer in Class 2 (adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.38-0.75, P = 2.32×10-4) and Class 3 (aHR = 0.67, 95% CI = 0.48-0.94, P = 0.022). In stratification analysis, we observed that the effects of Class 4 on lung cancer risk vary among histological subtypes. Additionally, within the Class 1 population, the top quintile of BMI also demonstrated different effects among histological subtypes. Increasing lifetime BMI was associated with a decreased risk of lung cancer, with this association varying by histological subtypes, indicating histology-specific mechanisms in lung carcinogenesis.

Keywords: body mass index; growth mixture modeling; lung cancer; trajectory

DOI: https://doi.org/10.1093/aje/kwaf084