bims-stacyt 2025-04-06 papers

Redox Biol. 2025 Mar 27. pii: S2213-2317(25)00126-0. [Epub ahead of print]82 103613

Repression of oxidative phosphorylation by NR2F2, MTERF3 and GDF15 in human skin under high-glucose stress.

Lifestyle factors such as a Western diet or metabolic diseases like diabetes disrupt glucose homeostasis and induce stress responses, yet their impact on skin metabolism and structural integrity remains poorly understood. Here, we performed multiomic and bioenergetic analyses of human dermal fibroblasts (HDFs), human equivalent dermis (HED), human reconstructed skin (HRS), and skin explants from diabetic patients. We found that 12 mM glucose stress represses oxidative phosphorylation (OXPHOS) through a dual mechanism: the glucose-dependent nuclear receptor NR2F2 activates mitochondrial transcription termination factor 3 (MTERF3) while inhibiting growth-differentiation factor 15 (GDF15). Promoter assays revealed that MTERF3 is regulated by NR2F2 and MYCN, whereas GDF15 is modulated by NR2F2 and FOS. Consequently, OXPHOS proteins and mitochondrial respiration were suppressed, and MTERF3 overexpression additionally interfered with collagen biosynthesis. In contrast, GDF15 supplementation fully rescued hyperglycemia-induced bioenergetic and metabolomic alterations, suggesting a pharmacological strategy to mitigate hyperglycemic damage in the skin. Finally, silencing GDF15 or TFAM impaired fibroblast haptotaxis and skin reconstruction, underscoring the crucial role of mitochondrial energetics in dermal structure and function. Collectively, these findings identify the NR2F2-MTERF3-GDF15 axis as a key mediator of OXPHOS suppression and highlight a potential therapeutic target to preserve skin integrity under hyperglycemic stress.

Keywords: GDF15; Hyperglycemia; MTERF3; Oxidative phosphorylation; Skin

DOI: https://doi.org/10.1016/j.redox.2025.103613

Cell Metab. 2025 Mar 26. pii: S1550-4131(25)00105-6. [Epub ahead of print]

Ceramide-induced FGF13 impairs systemic metabolic health.

Ceramide accumulation impairs adipocytes' ability to efficiently store and utilize nutrients, leading to energy and glucose homeostasis deterioration. Using a comparative transcriptomic screen, we identified the non-canonical, non-secreted fibroblast growth factor FGF13 as a ceramide-regulated factor that impairs adipocyte function. Obesity robustly induces FGF13 expression in adipose tissue in mice and humans and is positively associated with glycemic indices of type 2 diabetes. Pharmacological or genetic inhibition of ceramide biosynthesis reduces FGF13 expression. Using mice with loss and gain of function of FGF13, we demonstrate that FGF13 is both necessary and sufficient to impair energy and glucose homeostasis independent of ceramides. Mechanistically, FGF13 exerts these effects by inhibiting mitochondrial content and function, metabolic elasticity, and caveolae formation, which cumulatively impairs glucose utilization and thermogenesis. These studies suggest the therapeutic potential of targeting FGF13 to prevent and treat metabolic diseases.

Keywords: FGF13; adipocytes; ceramides; diabetes; insulin resistance; lipotoxicity; obesity; sphingolipids

DOI: https://doi.org/10.1016/j.cmet.2025.03.002

Discov Oncol. 2025 Apr 02. 16(1): 453

Role of metabolic transformation in cancer immunotherapy resistance: molecular mechanisms and therapeutic implications.

Sandesh Shende, Jaishriram Rathored, Tanushree Budhbaware.

BACKGROUND: Immunotherapy in the treatment of cancer, with immune inhibitors helps in many cancer types. Many patients still encounter resistance to these treatments, though. This resistance is mediated by metabolic changes in the tumour microenvironment and cancer cells. The development of novel treatments to overcome resistance and boost immunotherapy's effectiveness depends on these metabolic changes.
OBJECTIVE: This review concentrates on the molecular mechanisms through which metabolic transformation contributes to cancer immunotherapy resistance. Additionally, research therapeutic approaches that target metabolic pathways to enhance immunotherapy for resistance.
METHODS: We used databases available on PubMed, Scopus, and Web of Science to perform a thorough review of peer-reviewed literature. focusing on the tumor microenvironment, immunotherapy resistance mechanisms, and cancer metabolism. The study of metabolic pathways covers oxidative phosphorylation, glycolysis, lipid metabolism, and amino acid metabolism.
RESULTS: An immunosuppressive tumour microenvironment is produced by metabolic changes in cancer cells, such as dysregulated lipid metabolism, enhanced glutaminolysis, and increased glycolysis (Warburg effect). Myeloid-derived suppressor cells and regulatory T cells are promoted, immune responses are suppressed, and T cell activity is impaired when lactate and other metabolites build up. changes in the metabolism of amino acids in the pathways for arginine and tryptophan, which are nutrients crucial for immune function. By enhancing their function in the tumour microenvironment, these metabolic alterations aid in resistance to immune checkpoint inhibitors.
CONCLUSION: Metabolic change plays a key role in cancer immunotherapy resistance. Gaining knowledge of metabolic processes can help develop efficient treatments that improve immunotherapy's effectiveness. In order to determine the best targets for therapeutic intervention, future studies should concentrate on patient-specific metabolic profiling.

Keywords: Amino acid metabolism; Cancer metabolism; Glycolysis; Immune checkpoint inhibitors; Immunotherapy resistance; Tumour microenvironment

DOI: https://doi.org/10.1007/s12672-025-02238-3

Immunity. 2025 Mar 21. pii: S1074-7613(25)00096-2. [Epub ahead of print]

Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer.

The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restores anti-tumor immunity and re-sensitizes the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlates with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.

Keywords: arachidonic acid; extracellular vesicles; immunotherapy; neutrophils; triple negative breast cancer

DOI: https://doi.org/10.1016/j.immuni.2025.03.002

J Immunol. 2025 Apr 03. pii: vkaf045. [Epub ahead of print]

The metabolic drivers of IFN-γ release: glycolysis and acetyl CoA ride in the front seat.

John Henderson, Steven O'Reilly.

Interferon gamma (IFN-γ) is a pleotropic cytokine which is a central mediator of the immune response to pathogen infection, while also playing important roles in tumour suppression and the pathogenesis of various autoimmune diseases. Consequently, there is potential utility in the treatment of a number of pathological conditions via being able to modify IFN-γ secretion. T cells and natural killer (NK) cells are the primary IFN-γ sources, with metabolic rewiring prior to their activation and IFN-γ secretion in both a unifying feature. The mechanisms by which metabolic changes, particularly increased glycolysis, drive enhanced IFN-γ production are multi-faceted, but are likely focused on epigenetic changes via increased acetyl CoA levels which fuels histone acetylation. Herein, we discuss the mechanisms by which metabolic changes drive altered IFN-γ synthesis by immune cells.

Keywords: STING; acetyl CoA; glycolysis; immunometabolism; interferon

DOI: https://doi.org/10.1093/jimmun/vkaf045