bims-meluca 2026-08-23 papers

Front Immunol. 2026 ;17 1885023

IL-6 signaling orchestrates proteolytic hubs MuRF1 and Atrogin-1 in NSCLC induced sarcopenia.

Non-small cell lung cancer (NSCLC) is frequently associated with sarcopenia, a debilitating condition of muscle wasting driven by complex tumor-muscle cross-talk. To unravel the regulatory mechanisms underlying this phenotype, we reconstructed a comprehensive signaling network integrating inflammatory, anabolic, catabolic, and proteolytic pathways. The network was translated into a mechanistic mathematical model using ordinary differential equations, enabling dynamic simulations of pathway activity. Flux analysis revealed that only a limited number of reactions dominate system behavior, with cytoplasmic IL-6 export and SMAD2/3-4 mediated induction of MuRF1 and Atrogin-1 emerging as major control points for muscle protein breakdown. Crosstalk analysis identified these proteolytic regulators as central hubs, integrating signals from inflammatory cytokines, oxidative stress, and transcriptional modulators. Principal component analysis further confirmed that sarcopenic progression is governed by a compact regulatory core, with IL-6/STAT3, myostatin/SMAD, and FOXO/NF-κB pathways converging on MuRF1 and Atrogin-1. Experimental validation using immunofluorescence-based confocal microscopy demonstrated increased expression and altered localization of these ubiquitin ligases in C2C12 cells co-cultured with lung cancer lines, corroborating model predictions. Together, these findings provide a systems-level framework that transforms broad observations of inflammation into ranked therapeutic targets and support combined strategies aimed at blocking the IL-6/STAT3-myostatin/SMAD-FOXO1/3-MuRF1/Atrogin-1 axis to mitigate NSCLC-associated sarcopenia.

Keywords: Atrogin-1; IL-6; MuRF1; NSCLC; sarcopenia; signaling; therapeutics

DOI: https://doi.org/10.3389/fimmu.2026.1885023

Front Aging. 2026 ;7 1800359

The relationship between sarcopenia detected in newly diagnosed lung cancer patients and serum levels of IL6, IGF-1 and myostatin.

Kamil Süzer, Utku Oflazoglu, Leyla Demir, Sinan Unal, Zeynep Gulsum Guc, Yasar Yildiz, Furkan Oguzhan Karalar, Yuksel Kucukzeybek, Ahmet Alacacioglu.

Aim: Sarcopenia can result from many factors, including cancer, and is a consequence of quantitative and qualitative deterioration in skeletal muscle mass. Although there are some hypothetical explanations for sarcopenia, the underlying mechanisms of this condition have not been clearly defined in cancer patients. In this study, we aimed to investigate the association between sarcopenia and serum levels of myostatin, insulin-like growth factor-1 (IGF-1), and interleukin-6 (IL-6) in patients with newly diagnosed lung cancer.
Material and Method: This cross-sectional prospective study included patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC), who were categorized into two groups based on the presence or absence of sarcopenia. Body composition and muscle mass were evaluated using bioelectrical impedance analysis (BIA), and body mass index (BMI) was calculated. Handgrip strength was measured using a handheld dynamometer. Serum levels of myostatin, insulin-like growth factor-1 (IGF-1), and interleukin-6 (IL-6) were analyzed from fasting venous blood samples to assess their association with sarcopenia.
Results: A total of 69 patients were included in the study. The patients' ages ranged from 49 to 75 years. Thirty-four of these patients were sarcopenic and thirty-five of them were non-sarcopenic. Eighty-seven percent (60) of the patients included in the study were male. While myostatin and IL-6 levels were higher in the sarcopenic patient group, IGF-1 mean levels were lower. In the non-sarcopenic patient group, the median levels of myostatin, IL-6, and IGF-1 were 11.82 ng/mL, 1.17 pg/mL and 23.51 ng/mL, respectively. In the sarcopenic patient group, the median levels of myostatin, IL-6, and IGF-1 were 16.76 ng/mL, 7.42 pg/mL and 12.82 ng/mL, respectively (p < 0.001, p < 0.01, and p < 0.001, respectively). Spearman's correlation analysis between SMI (skeletal muscle mass index) and myostatin, IGF-1 and IL-6 levels showed a negative correlation of SMI with myostatin and IL-6, and a positive correlation with IGF-1 [(r = -0.436, p < 0.001) (r = -0.520, p < 0.001), (r = 0.219, p:0.071) respectively]. When a logistic regression model was constructed with sarcopenia status as the dependent variable and myostatin, IGF-1, IL-6, and ECOG performance parameters as independent variables, myostatin and IGF-1 were identified as independent predictors [OR: 1.332, CI: (1.128-1.574), p: 0.001; OR: 0.926, CI: (0.874-0.982), p: 0.01, respectively].
Conclusion: We found a significant correlation between sarcopenia and myostatin, IGF-1 and IL-6 in patients with lung cancer. We suggest that myostatin, IGF-1, and potentially IL-6 may serve as reliable markers for sarcopenia in cancer patients. We believe that these findings may encourage future prospective studies investigating the potential relevance of myostatin, IGF-1 and IL-6 as markers of sarcopenia.

Keywords: IGF-1; IL-6; bio-electric impedance analysis; lung cancer; myostatin; sarcopenia

DOI: https://doi.org/10.3389/fragi.2026.1800359

Cell Signal. 2026 Aug 19. pii: S0898-6568(26)00488-2. [Epub ahead of print] 112830

The O-glycosylation of SH3PX1 accelerates the progression of lung adenocarcinoma by modulating cell proliferation and glycolysis.

Siyao Wang, Yingqi Tang, Yegang Ma, Pengfei Li.

Lung adenocarcinoma (LUAD) remains a significant clinical challenge due to its high rate of recurrence, and the molecular mechanisms driving its malignant progression remain incompletely understood. The functional role of SH3PX1 in LUAD was assessed using in vitro assays (CCK-8, colony formation, EdU, cell cycle, and metabolic assays) as well as in vivo xenograft models. Bioinformatic analysis revealed that SH3PX1 is upregulated in LUAD, and its elevated expression is associated with poor patient prognosis. In LUAD cell lines, overexpression of SH3PX1 promoted cell proliferation and glycolysis, whereas SH3PX1 knockdown produced the opposite effects. Moreover, SH3PX1 enhanced tumor growth in vivo. Mechanistically, SH3PX1 was identified to interact with GALNT2, a key enzyme responsible for initiating protein O-glycosylation. We further demonstrated that the stability of SH3PX1 was regulated by GALNT2-mediated O-glycosylation at serine 92 (S92). Additionally, the pro-tumorigenic effects of GALNT2 on LUAD cell malignancy were suppressed upon SH3PX1 knockdown, indicating that SH3PX1 serves as a downstream mediator of GALNT2 in LUAD pathogenesis. Collectively, these findings provide that SH3PX1 acts as a regulator of LUAD malignancy through GALNT2-mediated O-glycosylation and stabilization, suggesting that targeting SH3PX1 may represent a potential therapeutic strategy for LUAD.

Keywords: GALNT2; Lung adenocarcinoma; O-glycosylation; SH3PX1

DOI: https://doi.org/10.1016/j.cellsig.2026.112830

Discov Oncol. 2026 Jul 25. pii: 1226. [Epub ahead of print]17(1):

Identification of disulfidptosis-related molecular subtypes in pleural mesothelioma demonstrates a correlation with the immune infiltration, prognosis and therapy efficacy.

Jing Ding, Xuefeng Huang, Wenxiu Yao, Tongyu Lin.

BACKGROUND: Pleural mesothelioma (PM) is a rare and aggressive malignancy with increasing incidence, high mortality, and limited treatment options. Disulfidptosis, a newly identified form of regulated cell death, may play an important role in cancer, but its relevance in PM remains unclear.
METHODS: Transcriptomic and clinical data of PM were obtained from public databases. PM was classified into molecular subtypes based on disulfidptosis-related genes (DRGs). We then compared prognosis, tumor microenvironment, metabolic features, predicted response to immune checkpoint blockade, and chemotherapy sensitivity between subtypes. In addition, a prognostic signature was established, and key genes were identified using random survival forest analysis.
RESULTS: Two novel DRG-defined molecular subtypes were identified in PM. The DRGs-high subtype (Cluster 2) was associated with significantly worse overall survival, an immunosuppressive microenvironment dominated by M2 macrophages, and a lower predicted likelihood of response to immune checkpoint blockade. In contrast, the DRGs-low subtype (Cluster 1) showed metabolic reprogramming toward glycolysis and fatty acid oxidation, increased NK cell infiltration, and reduced sensitivity to chemotherapy. An 11-gene prognostic signature demonstrated predictive performance, with an AUC of 0.95 for 5-year survival (95%CI 0.881-1.013). Random survival forest analysis identified LMNB2 and CDCA2 as key genes, both of which were highly expressed in tumor tissues.
CONCLUSIONS: PM can be classified into two DRG-defined molecular subtypes with distinct prognostic, immune, and metabolic features. These findings provide insights into PM heterogeneity and may support future studies on therapeutic stratification. The prognostic signature remains exploratory and requires validation in independent external cohorts before clinical application.

Keywords: Disulfidptosis; Molecular subtypes; Pleural mesothelioma; Prognostic signature; Tumor microenvironment

DOI: https://doi.org/10.1007/s12672-026-05557-1

Nat Metab. 2026 Aug;8(8): 1772-1790

Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism.

Zhongchi Li, Shuchen Liu, Wenbing Jin, Leyi Xiao, Olivia Kester, Nayah Bullen, Xuanrong Chen, Un In Chan, Jude Owiredu, Zhucui Li, Rabia Khan, Jennifer Endress, Moniquetta Shafer, Vivien Low, Nikolaos Koundouros, Sungyun Cho, Christopher Barbieri, Chun-Jun Guo, John Blenis.

Enhanced cholesterol synthesis and lipid droplet accumulation are hallmarks of aggressive prostate cancer, yet how tumour cells sense metabolic inputs to dynamically regulate cholesterol homeostasis remains poorly defined. Here we uncover a metabolic signalling mechanism in which prostate cancer cells remodel propionyl-CoA metabolism to support stress adaptation during disease progression. We show that the catabolism of branched-chain amino acid, specifically isoleucine and valine, is the primary source of intracellular propionyl-CoA in prostate cancer cells. Beyond its metabolic role, propionyl-CoA functions as a signalling molecule that stabilizes nuclear sterol regulatory element-binding protein 2 (SREBP2) through site-specific lysine propionylation, thereby enhancing its transcriptional activity. This activation promotes cholesterol biosynthesis, fuels de novo androgen production, and sustains androgen receptor signalling under metabolic and therapeutic stress, including androgen deprivation. Together, our findings establish propionyl-CoA as a key metabolic signal linking amino acid catabolism to cholesterol-driven oncogenic programmes and highlight targeting isoleucine and valine metabolism as a potential strategy to disrupt lipid reprogramming in prostate cancer.

DOI: https://doi.org/10.1038/s42255-026-01583-z