bims-stacyt 2025-08-24 papers

Nat Metab. 2025 Aug 18.

Metabolic Messenger: growth differentiation factor 15.

Growth differentiation factor 15 (GDF15; also known as macrophage-inhibitory cytokine-1) is a stress-responsive cytokine that is overexpressed under a broad range of conditions. It has a role in regulating appetite and body weight and is an aetiological factor in anorexia-cachexia syndromes, as well as nausea and vomiting during pregnancy. Long after its original cloning, its receptor was identified as GFRAL, a distant member of the GDNF receptor family within the TGFβ superfamily, with RET as its co-receptor. Both of these are highly localized to specific hindbrain regions. Although many of GFRAL's metabolic changes may be linked to its effect on suppressing appetite, recent findings suggest that GDF15 also independently regulates energy expenditure and insulin sensitivity. Here, we review recent literature and provide updates on the current understanding of GDF15 biology and its therapeutic applications in health and metabolic diseases.

DOI: https://doi.org/10.1038/s42255-025-01353-3

Mol Carcinog. 2025 Aug 19.

Elevated Polyamine Metabolism Activates Fibroblasts via GCN2 Activation and Generates Senescent Fibroblasts to Promote Tumor Formation and Progression.

Eric T Alexander, Katherine S Barone, Susan K Gilmour.

GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine in the tissue microenvironment activates GCN2 and alters stromal cell metabolism to support tumor cell survival and drive myeloid immunosuppressive function. To study the effect of elevated polyamine metabolism on fibroblast activation, we used the K6/ODC transgenic model of carcinogen-initiated, polyamine-promoted skin carcinogenesis. GCN2 loss significantly delayed tumor development and decreased tumor number and tumor burden in K6/ODC; GCN2-/- mice compared that in K6/ODC mice. Underlying dermal fibroblasts from nontumor bearing K6/ODC mice express elevated levels of genes associated with GCN2 activation and fibroblast activation. Expression of these genes was not elevated in K6/ODC; GCN2-/- dermis. In addition, K6/ODC mice have significantly more myeloid derived suppressor cells (MDSC) compared to normal littermates, and MDSCs were decreased in K6/ODC mice deficient in GCN2. Dermal fibroblasts cultured from K6/ODC transgenic mouse skin secrete increased levels of protumorigenic factors including senescence associated secretory phenotype (SASP) factors that stimulate invasiveness of stem-like epidermal tumorspheres as well as the polarization of M2-like macrophages. Using K6/ODC; p16-3MR mice in which senescent fibroblasts can be eliminated with ganciclovir treatment, carcinogen-initiated tumor development was greatly inhibited when senescent fibroblasts were eliminated in K6/ODC; p16-3MR mice. Our studies suggest a new paradigm in which cellular stress responses resulting from increased polyamine biosynthesis accelerate fibroblast activation and a senescence phenotype to create a protumorigenic microenvironment.

Keywords: GCN2; activated fibroblasts; polyamines; senescence; skin tumor promotion

DOI: https://doi.org/10.1002/mc.70034

Sci Rep. 2025 Aug 17. 15(1): 30138

Characterization of growth differentiation factor 15 (GDF15) as a neurotropic adipokine permeable to the brain.

Andreas Schmid, Emily Wilfurth, Alexandra Höpfinger, Manuel Behrendt, Edita Islami, Thomas Karrasch, Martin Berghoff, Andreas Schäffler.

GDF15 (growth/differentiation factor-15) belongs to the superfamily of transforming growth factor-beta. Little is known about adipocytic regulation of GDF15, its concentrations in serum and cerebrospinal fluid (CSF), its permeability to the brain, and its correlation with neurological diseases. This knowledge is important for a potential and clinical role of GDF15 as a mediator of the fat-brain axis in metabolic and neurological diseases. GDF15 mRNA expression in 3T3-L1 adipocytes was measured by qPCR and GDF15 protein levels in supernatants, serum and CSF were determined by ELISA. In vitro, GDF15 expression is nearly absent in pre-adipocytes and strongly upregulated during adipocyte differentiation. Insulin upregulates GDF15 secretion in adipocytes under normo- and hyperglycemic conditions. In vivo, we quantified GDF15 protein concentrations in paired samples of serum and CSF in a large and well-characterized clinical cohort of n = 390 patients undergoing neurological investigation and spinal puncture. This broad data set could serve as a basis for the development of GDF15 reference values in serum and CSF. GDF15 is highly permeable to the brain according to a specific CSF / serum ratio of 306 × 10-3. GDF15 is significantly increased in overweight and type 2 diabetic patients and correlates positively with serum glucose and HbA1c. GDF15 in CSF is elevated in patients with increased CSF cell count and impaired blood-brain-barrier function. Among five subsets of neurological diagnoses, GDF15 is exclusively increased in CSF and serum of patients with infectious diseases. GDF15 represents a promising adipokine and mediator of the fat-brain-axis that is co-regulated with metabolic factors and elevated in neurological patients with infectious diseases.

Keywords: Adipocyte; Adipokine; Adipose tissue; Cerebrospinal fluid; Fat-Brain axis; GDF15

DOI: https://doi.org/10.1038/s41598-025-14846-8

J Transl Med. 2025 Aug 18. 23(1): 923

Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression.

Xiaodie Liu, Heming Sun, Jing Liang, Huan Yu, Ming Xue, Yuebo Li, Wenhui Li, Ying Xu, Bin Ling, Dingqing Feng.

Tumor-associated macrophages (TAMs), abundant within the tumor microenvironment, are key mediators of immunosuppression and represent promising therapeutic targets. Metabolic crosstalk between tumor cells and TAMs is a critical regulator of immune phenotype switching. However, the interactions between endometrial cancer (EC) cells and TAMs remain incompletely understood. Here, we demonstrate that EC cells exhibit increased aerobic glycolysis, as confirmed by bulk transcriptomics, extracellular lactate measurements, RT-PCR, and immunohistochemistry. M2-polarized TAMs were significantly more prevalent in EC tissues compared to normal endometrium, and this prevalence correlated with deep myometrial invasion and advanced stages. In vitro assays revealed that EC cell-derived lactate promotes M2 polarization of macrophages, enhancing epithelial-mesenchymal transition and angiogenesis, thereby increasing EC cell invasiveness and metastasis. Cytokine profiling and functional assays further demonstrated that lactate-stimulated M2 TAMs secrete elevated IL-6, which promotes tumor progression. Importantly, blocking IL-6 signaling significantly reduced the M2 TAM-mediated effects on EC cells in vitro and inhibited tumor growth and metastasis in vivo. Our study underscores the pivotal role of aerobic glycolysis-derived lactate in inducing TAM M2 polarization and highlights the IL-6 axis as a therapeutic target, offering new strategies for treating EC by disrupting metabolic-immune crosstalk.

Keywords: Aerobic glycolysis; Angiogenesis; Endometrial cancer; Epithelial-mesenchymal transition; IL-6; Lactate; Metabolism reprogramming; Tumor-associated macrophages

DOI: https://doi.org/10.1186/s12967-025-06235-6

Cell Death Discov. 2025 Aug 19. 11(1): 390

The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.

Xing Yan, Changhong Liu.

At the center of tumor(neoplasm) metabolic adaptation lies activating transcription factor 4 (ATF4), a key regulator that orchestrates Glutamine (Gln) uptake, utilization, and redox balance under conditions of nutrient deprivation and oxidative stress. This review explores how ATF4 integrates environmental and cellular stress signals to drive Gln metabolic processes, enabling tumor survival, metabolic reprogramming, and immune evasion. The ATF4-Gln axis emerges as a pivotal vulnerability in cancer metabolic processes. Preclinical studies of small-molecule inhibitors and synthetic derivatives disrupting this pathway show promising results. Understanding the intricate interplay between ATF4, Gln metabolic processes, and cancer progression provides valuable insights for novel therapeutic strategies. Future research must address tumor heterogeneity and metabolic flexibility to fully harness the potential of ATF4-centered therapies. However, challenges such as off-target effects of ATF4 inhibitors and metabolic plasticity in tumors remain critical barriers. Future studies integrating multi-omics approaches and AI-driven drug discovery are warranted to overcome these hurdles.

DOI: https://doi.org/10.1038/s41420-025-02683-7