bims-meluca 2026-10-25 papers

Cell Mol Life Sci. 2026 Oct 19. pii: 389. [Epub ahead of print]83(1):

Lung cancer metabolism: a dynamic and adaptive network.

Sara Gholamhosseinian-Najjar, Christian Frezza.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Although substantial progress has been made in defining the genetic, epigenetic, and molecular drivers of this heterogeneous disease, metabolic reprogramming has only recently emerged as a major determinant of tumour progression and therapeutic response. Cumulative evidence demonstrates that rather than relying on a single nutrient source or pathway, cancer cells integrate glucose and glutamine, fatty acid and one-carbon metabolism, as well as nucleotide biosynthesis, and redox-supporting circuits in a highly context-dependent manner. These programs vary across histological and molecular subtypes, reflecting the influence of lineage identity and oncogenic state on metabolic organisation. In both non-small cell lung cancer and small cell lung cancer, subtype-specific constraints shape distinct metabolic states, yet a common feature is the ability to rapidly shift between alternative nutrients and biosynthetic routes. This adaptability supports continued growth under nutrient limitation, maintains redox homeostasis, and contributes to resistance against conventional and targeted therapies. By summarising current mechanistic evidence, this review presents lung cancer metabolism as an integrated and adaptable system rather than a collection of isolated pathways, and identifies metabolic dependencies that may be leveraged for therapeutic intervention.

Keywords: Glucose metabolism; Glutamine metabolism; Lung cancer metabolism; Metabolic plasticity; Nucleotide metabolism; Sulphur metabolism.

DOI: https://doi.org/10.1007/s00018-026-06417-5

Cell. 2026 Oct 23. pii: S0092-8674(26)01186-4. [Epub ahead of print]

Cell-state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer.

Cellular heterogeneity and plasticity are hallmarks of cancer that contribute to tumor growth and therapy resistance. Here, we investigated metabolic heterogeneity in small cell lung cancer (SCLC), an aggressive cancer type with considerable plasticity between neuroendocrine (NE) and non-NE cellular states. Through integrated transcriptomic and metabolomic analyses, we identified a universal dependency on exogenous cysteine/cystine (Cys) across all NE/non-NE SCLC cell states. Notably, NE and non-NE cells with low ASCL1 transcription factor levels underwent ferroptosis upon Cys depletion, whereas ASCL1high cells underwent apoptosis while remaining resistant to ferroptosis. This ferroptosis resistance was driven by the direct transcriptional activation of GCH1 by ASCL1, resulting in increased levels of the antioxidants BH4/BH2. Accordingly, combined Cys depletion and inhibition of BH4/BH2 synthesis reduced tumor growth in patient-derived xenografts. These findings demonstrate that metabolic state influences cell-death susceptibility in SCLC and provide a rationale for therapeutic strategies that exploit these metabolic differences.

Keywords: ASCL1; GCH1; SCLC; apoptosis; ferroptosis; heterogeneity; lung cancer; metabolism; neuroendocrine; plasticity

DOI: https://doi.org/10.1016/j.cell.2026.09.045

J Proteome Res. 2026 Oct 02. 25(10): 5284-5304

Peroxiredoxin 6 Silencing Remodels Lipid Metabolism and Redox Pathways to Promote Ferroptosis-Mediated Radiosensitization in Nonsmall Cell Lung Cancer.

Debojyoti Pal, Raghavendra S Patwardhan, Santosh K Sandur.

Ionizing radiation (IR) induces oxidative stress and lipid peroxidation with ferroptosis contributing to radiation-induced cancer cell death. Peroxiredoxin 6 (PRDX6), a multifunctional enzyme involved in phospholipid repair and redox regulation, has been implicated in ferroptosis regulation, but its role in the radiosensitivity of cancer cells remains unclear. Here, we show that PRDX6 depletion enhances radiosensitivity in A549 lung cancer cells. PRDX6-silenced A549 cells exhibited elevated lipid peroxidation and labile iron levels, indicating a ferroptosis-prone state that was amplified by radiation. To identify the underlying drivers of ferroptosis sensitivity in the PRDX6 background, we performed global proteomic profiling of PRDX6-silenced A549 cells, with and without radiation. Basal PRDX6-deficient cells displayed increased levels of ACSL4 and DHCR7. ACSL4 activates peroxidation-prone polyunsaturated fatty acids for incorporation into membrane phospholipids, and DHCR7 depletes the antiferroptotic moiety, 7-dehydrocholesterol. MPST, an antioxidant protein, was downregulated. These changes were accentuated upon IR exposure with further suppression of GINS4, a negative regulator of ferroptosis. Functional rescue by oleic acid suggested the role of ACSL4 in the observed phenotypes. Radiosensitization via ferroptosis induction was additionally demonstrated in another human lung cancer cell line under the PRDX6-silenced state. Collectively, PRDX6 loss remodels the cellular proteome to establish a presensitized redox and lipid compositional state, which favors ferroptosis-driven radiosensitivity.

Keywords: ACSL4; GINS4; PRDX6; ferroptosis; lipid peroxidation; peroxiredoxin 6; radiation; radiosensitization

DOI: https://doi.org/10.1021/acs.jproteome.6c00317

Cell Death Dis. 2026 Jul 23. pii: 893. [Epub ahead of print]17(1):

SLC25A20 promotes tumor growth by reprogramming energy metabolism in lung adenocarcinoma.

Xing Liu, Xiaoyu Song, Cong Gan, Ye Wang, Mingxin Ni, Min Zhang, Shaodi Wen, Yahui Cao, Changhua Yi, Man Tian, Apeng Chen.

Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. The molecular alterations in tumors that promote metabolic diversity and distinct targetable dependencies remain poorly defined. The mitochondrial transporter SLC25A20, also known as carnitine-acylcarnitine translocase (CACT), is crucial for fatty acid β-oxidation (FAO) by importing acylcarnitines into the mitochondrial matrix. Here, we demonstrate that SLC25A20 is significantly upregulated in lung adenocarcinoma (LUAD) tissues and cells, and its expression correlates with poor patient survival. Gain- and loss-of-function experiments reveal that SLC25A20 promotes tumor cell proliferation, survival, migration, and invasion by enhancing FAO-associated mitochondrial bioenergetics and suppressing apoptosis. Mechanistically, SLC25A20-mediated FAO maintains mitochondrial function and supports oxidative phosphorylation (OXPHOS), thereby sustaining tumor bioenergetics and redox homeostasis. Pharmacological inhibition or genetic silencing of SLC25A20 impairs tumor growth in vivo. These findings establish SLC25A20 as a key metabolic driver in LUAD and suggest it may be a therapeutic target.

DOI: https://doi.org/10.1038/s41419-026-09119-9

Cancer Immunol Res. 2026 Oct 21.

Lower airway microbiome transcriptional and metabolic activities influence responsiveness to immunotherapy in NSCLC.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non-small cell lung cancer (NSCLC), yet a large proportion of patients do not respond. The lung microbiome is a key modulator of antitumor immunity, however, the functional contribution of active microbial communities and their interaction with host transcriptional programs in shaping ICI outcomes remain poorly defined. Here, we prospectively analyzed bronchoalveolar lavage (BAL) samples from 71 NSCLC patients prior to ICI initiation. We profiled the microbiome and host transcriptome in the BAL to look for microbial and host signatures in the lower airways associated with treatment response. We found that enrichment of the lower airway microbiome with oral commensals was associated with disease progression and worse prognosis of patients treated with ICI. Metatranscriptomics-derived microbial clustering revealed distinct functional profiles. The microbial cluster enriched with oral commensals, which was only present among patients with poor response to ICI, had differential regulation of pathways involved in the metabolism of short-chain fatty acids, methane, and pyruvate. This cluster also correlated with host immune pathways including upregulation of interferon signaling, neutrophil degranulation, and mitophagy, all of which could contribute to the poor response to immunotherapy. In a preclinical murine model of lung cancer with dysbiosis, inoculating lung tumor-bearing mice with oral commensals increased intratumoral neutrophils and Th17 responses and impaired ICI efficacy. Our findings support the concept that microbial communities in the lower airways influence tumor-immune interactions via defined metabolic-immune axes.

DOI: https://doi.org/10.1158/2326-6066.CIR-26-0433