bims-meluca 2026-10-11 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–10–11
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Stromal MTHFD2 Links Fibrotic Remodeling to Immune Evasion via Redox-Dependent Inflammatory Signaling in Lung Adenocarcinoma.
PRTN3 drives immunosuppression in KRAS-mutant lung adenocarcinoma through proteolytic inactivation of CXCL9.
Integrated miRNA-cytokine profiling reveals a molecular signature of cachexia in patients with chronic heart failure.
Icariin synergistically inhibits glycolysis and mitochondrial energy metabolism in lung cancer in association with the HIF-1α/LONP1 axis.
CDC73 suppresses lung adenocarcinoma via the PTEN/AKT pathway and exhibits biomarker and functional potential in extracellular vesicles.
L-Arginine inhibits NLRP3 inflammasome activation.

Cancer Res. 2026 Oct 05.

Stromal MTHFD2 Links Fibrotic Remodeling to Immune Evasion via Redox-Dependent Inflammatory Signaling in Lung Adenocarcinoma.

Ye Eun Hwang, Eunae You, Jinho Kim, Seula Keum, Jangho Jeong, Seongeun Song, Minwoo Lee, Sunghyun Kim, Chung-Hyun Cho, Mineui Hong, Jin Kyung Rho, Jung-Woong Kim, Sangmyung Rhee.

Fibroblast activation and extracellular matrix stiffening are hallmarks of the fibrotic tumor microenvironment. Fibrotic microenvironmental remodeling is also linked to immune exclusion and evasion, suggesting that common microenvironmental signals might coordinate both fibrotic and inflammatory outputs. Here, we identified methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) as a redox-sensitive metabolic regulator linking TGF-β-driven fibroblast activation to inflammatory signaling in lung adenocarcinoma (LUAD). MTHFD2 was elevated in cancer-associated fibroblasts across multiple scRNA-seq datasets, and TGF-β induced MTHFD2 even under compliant matrix conditions, with matrix stiffening further enhancing its expression. Notably, while MTHFD2 knockdown suppressed both myofibroblastic and inflammatory programs, enforced expression was sufficient to drive inflammatory cytokine production even in the absence of TGF-β, and this response was further amplified by concomitant TGF-β signaling. These MTHFD2-mediated responses depended on redox perturbation rather than biosynthetic one-carbon metabolism, as they resisted formate supplementation but responded to pro-oxidants. Mechanistically, MTHFD2-driven redox imbalance promoted mitochondrial stress, cytosolic mitochondrial DNA accumulation, and activation of the cGAS-STING-NF-κB pathway, resulting in IL-6 and IL-8 production. Fibroblast-specific MTHFD2 knockdown suppressed paracrine PD-L1 induction in tumor cells and inhibited tumor growth in vivo in an immune-dependent manner. Clinically, high stromal MTHFD2 correlated with epithelial PD-L1 expression and poor LUAD prognosis. Together, these findings identify stromal MTHFD2 as a redox-sensitive metabolic checkpoint linking fibrotic remodeling to immune evasion.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0297
J Immunother Cancer. 2026 Oct 05. pii: e015399. [Epub ahead of print]14(10):

PRTN3 drives immunosuppression in KRAS-mutant lung adenocarcinoma through proteolytic inactivation of CXCL9.

Yi Liu, Chen Zhang, Jia Li, Chong Chen, Song Xu, Tong Li, Huilin Chen, Yigong Hou, Jiayu Jiang, Haojie Chen, Wei Wang, Rong Xiang, Renle Du, Yunping Luo.

   BACKGROUND: KRAS-mutant lung adenocarcinoma (LUAD) shows limited benefit from immune checkpoint blockade (ICB), and the mechanisms by which oncogenic KRAS signaling promotes immune resistance remain poorly understood. Here, we sought to identify tumor-intrinsic mediators of KRAS-driven immune evasion and therapeutic resistance in LUAD.
METHODS: Integrated analyses of human LUAD cohorts, genetically engineered mouse models, tumor cell models, and patient-derived organoids were performed to define the role of PRTN3 in immune regulation. PRTN3 regulation and function were investigated using transcriptional analyses, chromatin immunoprecipitation assays, biochemical cleavage assays, and immune cell co-culture systems. The therapeutic effect of PRTN3 inhibition was evaluated using flow cytometric immune profiling, functional immune assays, and syngeneic tumor models.
RESULTS: We identified PRTN3 as a downstream effector of KRAS signaling that promotes immune evasion in LUAD. Mechanistically, KRAS signaling transcriptionally upregulated PRTN3 through c-Myc activation. Secreted PRTN3 directly cleaved and inactivated CXCL9 in the tumor microenvironment, disrupting CXCL9/CXCR3 signaling and impairing the recruitment and activation of cytotoxic CD8+ T cells and natural killer cells. In patients with LUAD, elevated PRTN3 expression was associated with reduced cytotoxic immune signatures and decreased CXCL9 activity. Genetic inhibition of PRTN3 enhanced antitumor immunity and improved responses to anti-programmed cell death protein 1 therapy in vivo. Furthermore, a hydrolysis-resistant CXCL9 variant restored cytotoxic lymphocyte activation and enhanced immune-mediated tumor cell killing in patient-derived organoids.
CONCLUSIONS: Our findings reveal a KRAS/c-Myc/PRTN3 axis that promotes immune suppression through extracellular proteolytic inactivation of CXCL9. Targeting PRTN3-mediated immune evasion may represent a promising strategy to enhance ICB efficacy in KRAS-driven LUAD.

Keywords:  Cytokine; Immunosuppression; Lung Cancer; T cell; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2026-015399
ESC Heart Fail. 2026 Aug 27. pii: xvag229. [Epub ahead of print]13(5):

Integrated miRNA-cytokine profiling reveals a molecular signature of cachexia in patients with chronic heart failure.

Federica Tambaro, Giovanni Imbimbo, Carmen Gallicchio, Paolo Nardozi, Simona Orlando, Roberta Belli, Cesarina Ramaccini, Stefan D Anker, Alessio Molfino, Maurizio Muscaritoli.

   INTRODUCTION: Cardiac cachexia (CC) complicates chronic heart failure (CHF). Circulating microRNAs (miRNAs) and cytokines, such as growth differentiation factor-15 (GDF-15) and fibroblast growth factor-21 (FGF-21), may reflect the catabolic-anabolic imbalance and structural remodelling associated with this syndrome. To define the circulating signature of CHF by profiling muscle and remodelling-related miRNAs alongside GDF-15 and FGF-21, and to assess their associations with cardiac function and clinical phenotypes.
METHODS: Twenty-five CHF patients (median age 78.0 years, 40% male) and 10 controls (median age 56.8 years, 60% male) were studied. CC was defined as unintentional, non-oedematous weight loss ≥6% within 6 months. Circulating miRNAs were quantified by RT-qPCR, GDF-15 and FGF-21 by ELISA. CHF patients were classified as having reduced (HFrEF) or preserved ejection fraction (HFpEF). Associations with CC and clinical CHF phenotypes were evaluated.
RESULTS: Compared with controls, CHF patients showed lower levels of miR-15b, miR-29b, miR-133a, and miR-486 (all P < .01) and elevated GDF-15 levels (P < .001). FGF-21 was higher in patients with CC (P = .012), in HFrEF vs HFpEF (P = .039), and in NYHA III-IV vs I-II (P = .05). miR-29b levels were lower in CC (P = .019) and in HFrEF + CC vs HFpEF + nCC (P = .019). In CC, FGF-21 inversely correlated with miR-486 (ρ = -.69, P = .035), whereas GDF-15 inversely correlated with miR-21 (ρ = -.81, P = .007).
CONCLUSIONS: CHF is associated with miRNA suppression and elevated stress cytokine levels, amplified in CC. miR-29b and FGF-21 showed associations with CC, functional impairment, and structural remodelling, warranting validation in larger longitudinal cohorts.

Keywords:  Cardiac cachexia; Cardiac remodelling; Chronic heart failure; FGF-21; GDF-15; microRNA

DOI:  https://doi.org/10.1093/eschf/xvag229
Tissue Cell. 2026 Oct 03. pii: S0040-8166(26)00711-1. [Epub ahead of print]104(Pt 3): 104015

Icariin synergistically inhibits glycolysis and mitochondrial energy metabolism in lung cancer in association with the HIF-1α/LONP1 axis.

Hongbo Zheng, Bojia Li, Junlei Chen, Tunan Ding, Peiyao Qin, Yidi Ma, Shunjingxiang Zhang, Xiang Li, Jiayi Li, Zhangkai Li, Xiaojie Zhou, Ruyang Li, Qiang Fu, Shuijie Li, Yin Fu.

   AIM OF THE STUDY: Non-small cell lung cancer (NSCLC) accounts for the vast majority of lung cancer cases and remains a therapeutic challenge due to drug resistance, adverse effects, and metabolic plasticity. Icariin (ICR), a principal bioactive flavonoid from Epimedium, exhibits promising antitumor properties; however, its precise role in modulating cancer energy metabolism remains poorly understood. This study aimed to investigate whether ICR synergistically inhibits glycolysis and mitochondrial metabolism, and whether these effects are associated with the HIF-1α/LONP1 signaling axis in NSCLC.
MATERIALS AND METHODS: In vitro functional assays were performed to evaluate cell proliferation, migration, invasion, apoptosis, and cell cycle progression in NSCLC cell lines. Integrative proteomics, targeted metabolomics, and Western blotting were employed to assess ICR-associated changes in HIF-1α, glycolytic enzymes (HK2, LDHA), and mitochondrial proteins (LONP1, TFAM, MTCO2). The in vivo antitumor efficacy and underlying metabolic mechanisms were validated using an A549 cell-derived xenograft model in nude mice.
RESULTS: ICR significantly suppressed proliferation, migration, and invasion while promoting apoptosis and G0/G1 cell cycle arrest in NSCLC cells. Multi-omics and biochemical analyses revealed that ICR attenuated both aerobic glycolysis and mitochondrial oxidative phosphorylation, accompanied by downregulation of HIF-1α, HK2, LDHA, LONP1, TFAM, and MTCO2. In vivo xenograft experiments confirmed that ICR treatment markedly inhibited tumor growth and modulated the expression of these key metabolic regulators, with no significant body weight loss observed.
CONCLUSION: This study demonstrates that ICR simultaneously suppresses glycolysis and mitochondrial energy metabolism, with these effects being associated with downregulation of the HIF-1α/LONP1 axis. These findings provide a novel mechanistic rationale and experimental foundation for metabolism-targeted therapeutic strategies in NSCLC.

Keywords:  Glycolysis; HIF-1α/LONP1 axis; Icariin; Lung cancer; Mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.tice.2026.104015
Cell Death Discov. 2026 Aug 14. pii: 412. [Epub ahead of print]12(1):

CDC73 suppresses lung adenocarcinoma via the PTEN/AKT pathway and exhibits biomarker and functional potential in extracellular vesicles.

Hao Dong, Yifan Zheng, Gaoming Wang, Xingyi Li, Jing Luo, Jingjing Feng, Xiaohui Zhu, Chongjun Zhong, Yiming Xu, Tian Xie, Yi Shen.

CDC73 is a canonical tumor suppressor; however, its biological functions in lung adenocarcinoma (LUAD) and the extracellular vesicle (EV)-mediated mechanisms through which it exerts its effects remain unclear. In this study, we systematically evaluated the diagnostic value, biological functions, and EV-mediated regulatory roles of CDC73 in LUAD. First, quantitative proteomic analysis was performed on plasma-derived EVs from six patients with early-stage LUAD and three healthy donors, followed by further validation of EV-borne CDC73 expression in plasma-derived EV samples from eight LUAD patients and eight healthy donors. We found that the level of EV-borne CDC73 protein (EV-CDC73) was significantly reduced in LUAD, indicating its potential value as a diagnostic liquid-biopsy biomarker. To define its functional role, we established LUAD cell lines stably overexpressing CDC73 (A549^OE and H1299^OE) and performed rescue experiments in combination with PTEN knockdown using siRNA. The tumor-suppressive effects of CDC73 were systematically assessed through experiments examining cell proliferation, cell-cycle progression, apoptosis, migration, and related molecular mechanisms. Meanwhile, EVs were isolated by ultracentrifugation from the conditioned media of A549, H1299, and human bronchial epithelial (HBE) cells to analyze the effects of EVs with different CDC73 levels on recipient A549 and HBE cells, and xenograft models were used for in vivo validation. The results showed that CDC73 overexpression markedly inhibited LUAD cell proliferation and migration, induced G1-phase arrest, and promoted apoptosis. Mechanistically, CDC73 exerted its tumor-suppressive effects by upregulating PTEN and inhibiting AKT activation, whereas PTEN knockdown partially reversed these effects. In vivo experiments further confirmed that CDC73 overexpression suppressed tumor growth and migration. In addition, EVs derived from LUAD cells with high CDC73 expression showed a reduced ability to induce malignant transformation-related phenotypes in HBE cells and suppressed the PTEN/AKT signaling axis; conversely, EVs derived from HBE cells with high CDC73 expression inhibited the malignant progression of LUAD cells. Collectively, CDC73 suppresses the malignant progression of LUAD through the PTEN/AKT signaling axis, while EV-borne CDC73 not only has potential diagnostic value but also directly regulates malignant phenotypes in recipient cells, highlighting its translational potential in the diagnosis and treatment of LUAD.

DOI: https://doi.org/10.1038/s41420-026-03305-6
Nat Metab. 2026 Oct 06.

L-Arginine inhibits NLRP3 inflammasome activation.

Feng Liu, Wanxin Zhuang, Yuan Yang, Wenting Zhao, Chao Zhang, Siyuan Li, Xudong Liu, Qingyuan Cao, Shunguo Zhu, Bingyu Liu, Xiangyu Ma, Lintai Da, Chengjiang Gao.

Nutritional status and metabolic homeostasis are intricately associated with the inflammatory response. However, the direct mechanistic link between nutrition, metabolism and inflammation remains unclear. Here, we show that the amino acid L-arginine (L-Arg) is a potent endogenous inhibitor of the NLRP3 inflammasome, a central component of the inflammatory signalling pathway. We show that L-Arg binds directly to the Asp31 site of the NLRP3 protein, blocking its interaction with the adaptor ASC and subsequent inflammasome assembly and activation. L-Arg supplementation inhibits the NLRP3 inflammasome activation in macrophages, while deprivation promotes it. Treatment with L-Arg in mice alleviates monosodium urate crystal-induced arthritis and aluminium-induced peritonitis. In addition, L-Arg supplementation alleviates neuroinflammation and motor deficits in mouse models of Parkinson's disease, whereas L-Arg deprivation exacerbates pathology. In patients with Parkinson's disease, L-Arg levels are reduced in serum. Our study establishes L-Arg supplementation as a promising therapeutic avenue for managing NLRP3-driven inflammatory pathologies.

DOI: https://doi.org/10.1038/s42255-026-01636-3