bims-stacyt 2025-12-14 papers

Cancer Lett. 2025 Dec 08. pii: S0304-3835(25)00781-5. [Epub ahead of print]639 218209

Lactic acid promotes an MDSC-like phenotype via HIF1α stabilization with impact on prognosis in renal cell carcinoma.

Paradoxically, immune cell infiltration correlates with worse prognosis in renal cell carcinoma (RCC) patients, with tumor-associated myeloid cells playing a key role in tumor progression. However, little is known about factors driving their polarization. Here, we investigated the link between RCC-related glycolysis, hypoxia-inducible factor (HIF)1α-associated myeloid inflammation, and patient prognosis. TCGA data revealed a strong correlation between the expression of monocarboxylate transporter 4 (MCT4), the myeloid marker CD14 and patient survival in ccRCC patients. scRNAseq data confirmed high MCT4 expression in both tumor and myeloid cells, suggesting lactate transport. In vitro analyses proved lactate uptake by CD14+ monocytes, which stabilized HIF1α and induced an MDSC-like, HLA-DR low phenotype. In line, the HIF1α-stabilizing drug Roxadustat increased the number of CD14+ HLA-DR low cells. Lactate uptake also increased protein lactylation. To further investigate the interplay between RCC tumor and myeloid cells, we established a 3D spheroid co-culture model and analyzed the effects of MCT inhibitors. This 3D model reflected tumor-myeloid cell interactions, as spheroid-infiltrating myeloid cells exhibited spontaneous IL-6 secretion comparable to patient-derived RCC cultures. Inhibition of lactate secretion reduced lactate and IL-6 secretion while increasing CD14+ HLA-DR+ cells. These findings were validated in patient-derived RCC cultures treated with anti-glycolytic drugs. Our data dissect the intratumoral network of RCC and show that tumor-derived lactate promotes a pro-tumorigenic myeloid phenotype with low MHC-II but high immune-checkpoint, LOX-1 and S100A8/9 expression. Blocking MCT disrupts this interplay, offering a promising strategy to re-educate tumor-associated myeloid cells and enhance tumor immune surveillance.

Keywords: IL-6 signaling; Lactate metabolism; Myeloid-derived suppressor cells (MDSCs); Renal cell carcinoma (RCC); Tumor glycolysis; Tumor microenvironment; Tumor-associated myeloid cells

DOI: https://doi.org/10.1016/j.canlet.2025.218209

Eur J Pharmacol. 2025 Dec 10. pii: S0014-2999(25)01211-7. [Epub ahead of print]1011 178457

Targeting the integrated stress response with ISRIB enhances CREB/BDNF signaling and attenuates cognitive deficits in a rat model of vascular cognitive impairment.

Tian Zhao, Quanxin Liu, Jianzhou Chen, Wenjing Xie, Qinghua Jin, Bin Xiao.

The integrated stress response (ISR) has been implicated in cognitive decline associated with ageing and neurodegenerative diseases. Pharmacological inhibition of the ISR using the small-molecule ISRIB has demonstrated promising neuroprotective effects in several preclinical models. However, its potential therapeutic value in vascular cognitive impairment (VCI) remains largely unexplored. Here, we established a modified permanent bilateral carotid occlusion (2-VO) rat model of VCI and investigated the therapeutic potential of the ISRIB via microinjection in hippocampal dentate gyrus (DG). VCI rats exhibited elevated expression of vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), ionized calcium-binding adapter molecule 1 (Iba1), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), indicating successful establishment of the model. Behavioral assessments revealed that VCI rats exhibited impaired spatial, working, and recognition memory. Bioinformatic analysis highlighted ISR pathway activation in VCI. Furthermore, elevated phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) and activating transcription factor 4 (ATF4) protein levels in the DG confirmed ISR activation in the DG of VCI rats. VCI also reduced neuronal integrity, as evidenced by decreased Nissl body density. ISRIB treatment significantly improved cognitive performance, suppressed ATF4 expression, enhanced puromycin-labeled protein synthesis, and restored phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) signaling. Notably, ISRIB increased c-fos activation and upregulated synaptophysin and postsynaptic density protein 95 (PSD95) expression in the DG of VCI rats, indicating enhanced neuronal activity and synaptic function. Our results indicate that ISR activation contributes to hippocampal-dependent memory impairment in VCI. ISRIB effectively restores synaptic function and cognition, underscoring its therapeutic value and translational potential in treating VCI.

Keywords: Hippocampal dentate gyrus; Integrated stress response; Learning and memory; Vascular cognitive impairment

DOI: https://doi.org/10.1016/j.ejphar.2025.178457

Cells. 2025 Dec 02. pii: 1908. [Epub ahead of print]14(23):

A20 and TNIP-3 Reduce NF-κB-Mediated Paracrine Responses to Hypoxia/Hyperglycemia-Induced Endothelial Senescence.

Lara Russo, Serena Babboni, Serena Del Turco, Giuseppina Basta.

BACKGROUND: Hypoxia and ageing both involve impaired oxygen delivery, leading to oxidative damage, and endothelial cell (EC) dysfunction. In the presence of chronic hyperglycemia, these effects are amplified, accelerating EC senescence and vascular impairment.
METHODS: We assessed key mediators of inflammatory signalling and senescence, as well as transcriptional regulators responsive to oxidative stress in ECs exposed to high glucose (30.5 mmol/L) for 72 h under either normoxia (21% O2) or prolonged (16 h) hypoxia (2% O2) followed by 2 h of reoxygenation.
RESULTS: ECs exposed to high glucose and hypoxia developed a senescent phenotype, as indicated by increased expression of p21 and p16, and elevated β-galactosidase staining. Interestingly, hypoxia-induced senescence did not coincide with the classical senescence-associated secretory phenotype (SASP). Compared to normoxia, ECs exposed to hypoxia, particularly under high-glucose conditions, showed reduced NF-κB-driven proinflammatory secretome (MCP-1, IL-6, IL-8), downregulation of the NF-κB p50 subunit, and simultaneous upregulation of the angiogenic factor VEGF-A with downregulation of YAP-1, a key regulator of cell survival. Notably, we observed a strong upregulation of A20 and TNIP-3, two well-characterized negative regulators of NF-κB signalling.
CONCLUSIONS: Hypoxia-induced senescence did not trigger a typical inflammatory SASP. Although ECs enter a senescent state, they activate an anti-inflammatory response, suppressing NF-κB signalling and increasing the expression of its inhibitors, A20 and TNIP-3. This may reflect a non-canonical senescence response whose functional significance remains to be determined.

Keywords: A20; NF-κB; SASP; TNIP-3; aging; endothelial cells; hyperglycemia; hypoxia

DOI: https://doi.org/10.3390/cells14231908

J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70154

Adipose-Muscle Crosstalk in COPD Cachexia: Early Adipose Atrophy Drives Subsequent Muscle Wasting.

Takashi Shimada, Shotaro Chubachi, Keisuke Nishikawa, Tetsuya Arai, Hideto Iizuka, Shiro Otake, Kaori Sakurai, Junko Hamamoto, Mamoru Sasaki, Tomoki Maetani, Naoya Tanabe, Katsunori Masaki, Hiroki Kabata, Jun Miyata, Yoshitake Yamada, Masahiro Jinzaki, Hidetoshi Nakamura, Koichiro Asano, Koichi Fukunaga.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is frequently associated with cachexia, leading to poor prognoses and reduced quality of life. However, the mechanisms underlying adipose tissue atrophy, its pathological significance and its interaction with skeletal muscle remain poorly understood. We hypothesised that adipose tissue atrophy precedes muscle wasting in COPD-associated cachexia, and muscle atrophy progresses through adipose-muscle crosstalk.
METHODS: We analysed chest computed tomography scans of 185 patients with COPD to quantify the cross-sectional areas of the pectoralis muscle (PM), subcutaneous adipose tissue (SAT) and epicardial adipose tissue (EAT), and the percentage of low attenuation area (LAA%) as an index of emphysema. To elucidate the pathophysiological mechanisms underlying cachexia in COPD, we performed histological and molecular analyses of the lung, muscle and adipose tissues over time in a cigarette smoke-induced emphysema mouse model. Further, we used an in vitro culture system of differentiated adipocytes (3T3-L1) and myotubes (C2C12) to study the effects of cigarette smoke extract (CSE) on adipose-muscle interaction.
RESULTS: In patients with COPD, the areas of PM, SAT and EAT all demonstrated significant negative correlations with LAA%; notably, PM and EAT were independently associated with the extent of emphysematous changes. In the smoke-exposed murine model, adipose tissue atrophy was observed after 1 month of exposure, accompanied by increased expressions of IL-6 and IL-1β, macrophage infiltration and the upregulation of the lipolytic enzymes ATGL and HSL. The adipose atrophy had further progressed after 3 months of exposure, and the high expression of UCP1 was sustained, which suggested the browning of adipose tissue. Conversely, muscle atrophy was not evident at 1 month but became apparent after 3 months, coinciding with emphysema development. This was associated with the downregulation of the myogenic markers MyoD and Myogenin and the upregulation of the muscle degradation marker Atrogin-1. In vitro experiments revealed that CSE exposure reduced lipid droplet content and induced IL-6 and IL-1β expressions in adipocytes. Conditioned media from CSE-treated adipocytes triggered myotube atrophy and downregulated MyoD and Myogenin but upregulated Atrogin-1.
CONCLUSIONS: Our findings indicate that cigarette smoke-induced adipose tissue atrophy precedes muscle wasting, and alterations in adipose tissue may contribute to muscle atrophy progression. Adipose tissue dysfunction may be implicated in the development of cachexia in patients with COPD, highlighting its potential as a therapeutic target.

Keywords: adipose tissue atrophy; cachexia; chronic obstructive pulmonary disease; muscle wasting

DOI: https://doi.org/10.1002/jcsm.70154

Cell Rep. 2025 Dec 11. pii: S2211-1247(25)01450-0. [Epub ahead of print]44(12): 116678

Paracrine stimulation of brown adipose tissue vascularization by adipocyte O-GlcNAc signaling.

Luwen Li, Liwei Dong, Yaping Shan, Jintang Xie, Ting Song, Sai Zhang, Yun Kong, Shiqi Zhang, Chengwei Gu, Die Hu, Weijia Wang, Yunfan Yang.

Brown adipose tissue (BAT) is extensively vascularized, which is essential for its physiological activities. The molecular mechanism that underpins BAT vascularization, however, remains poorly understood. This study presents evidence that acute cold exposure induces an elevation in total protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) in BAT. Ablation of O-GlcNAc transferase in brown adipocytes drastically impairs BAT vascularization. Mechanistic studies demonstrate that O-GlcNAcylation of specificity protein 1 in brown adipocytes enhances its transcriptional activity toward kielin/chordin-like protein (Kcp). Secreted KCP subsequently promotes BAT angiogenesis by paracrine activation of bone morphogenetic protein signaling. Furthermore, boosting O-GlcNAc signaling with glucosamine supplementation effectively augments BAT vascularization and thermogenesis. These findings thus uncover a previously unrecognized role of adipocyte O-GlcNAc signaling in the metabolism-driven regulation of BAT vascularization and function.

Keywords: BMP signaling; CP: metabolism; KCP; O-GlcNAc; brown adipose tissue; vascular system

DOI: https://doi.org/10.1016/j.celrep.2025.116678

Cell Metab. 2025 Dec 05. pii: S1550-4131(25)00491-7. [Epub ahead of print]

Restricting lipid accumulation in tumor-infiltrating neutrophils mediates caloric restriction-induced anti-cancer effects.

Jian Gao, Wei Zhang, Qian Li, Dan Zhao, Jiayi Cai, Qing Wang, Xin Li, Tingting Liu, Jin Li, Wengan Xiao, Huimin Li, Min Du, Bing Zhang, Peiying Li, Hong Tu, Yu Gan.

Caloric restriction (CR) induces tumor resistance in mammals, but its mechanisms remain poorly understood. Here, we found that CR altered the proportions and gene expression profiles of tumor-infiltrating neutrophils (TINs). Depletion of neutrophils largely abrogated CR-induced tumor inhibition across multiple murine cancer models, underscoring their critical role in CR's broad anti-tumor effect. CR-induced gene expression changes in TINs were associated primarily with lipid-related processes, notably downregulating hypoxia-inducible lipid droplet-associated (HILPDA). This downregulation reduced lipid accumulation in TINs, limiting tumor growth and enhancing anti-tumor immunity by decreasing lipid transfer to tumor and immune effector cells. Upstream, CR reduced hypoxia-inducible factor 1 (HIF-1α) mRNA expression in circulating neutrophils by decreasing insulin-like growth factor 1 (IGF-1), thereby limiting HILPDA expression in TINs. Patients with lung cancer who had low baseline neutrophil HIF-1α mRNA exhibited improved responses to combined immunotherapy. These findings identify a novel neutrophil- and lipid-centered mechanism for CR-induced tumor inhibition, suggesting the IGF-1/HIF-1α/HILPDA axis as a therapeutic target.

Keywords: HIF-1α; HILPDA; IGF-1; anti-cancer effect; caloric restriction; lipid accumulation; neutrophil

DOI: https://doi.org/10.1016/j.cmet.2025.11.007