bims-stacyt 2026-01-04 papers

Front Immunol. 2025 ;16 1683249

ATF4 promotes renal tubulointerstitial fibrosis through hexokinase II-mediated glycolysis.

Songtao Feng, Yueming Gao, Zheng Wang, Weijie Ni, Yan Zhou, Mingyue Yuan, Jinyang Ge, Lu Sun, Bicheng Liu, Hui Qian, Zuolin Li.

Background: Renal tubulointerstitial fibrosis is a reliable predictor of progressive chronic kidney disease (CKD). Activating transcription factor 4 (ATF4) has recently emerged as a pivotal player in multiple pathophysiologic processes, particularly the stress response processes. This study aims to explore the role of ATF4 in tubulointerstitial fibrosis from a metabolic perspective.
Methods: A murine model of renal fibrosis was generated via unilateral ureteral obstruction (UUO). Quantitative PCR was employed to assess the expression of inflammation-related genes and fibrotic markers in renal tissue, while Western blotting was used to quantify the corresponding protein levels. Immunohistochemistry was performed to determine the localization and expression patterns of ATF4. Lentivirus-mediated ATF4 knockdown mice, along with mice subjected to glycolytic inhibition, were subsequently employed to further investigate their effects on inflammatory mediators and fibrotic markers. In parallel, human renal proximal tubule epithelial cells (HK-2) were exposed to transforming growth factor-β1 (TGF-β1) to induce fibrosis in vitro. Subsequent molecular assays were performed to confirm the regulatory relationship between ATF4 and hexokinase II (HK-II), including verification of ATF4 binding to the HK2 promoter.
Results: Western blotting and PCR analyses revealed a pronounced elevation of inflammatory cytokines, fibrotic markers, and ATF4 in the renal tissues of UUO mice compared with sham controls. Both in vitro and in vivo, ATF4 knockdown markedly mitigated tubular epithelial injury and fibrosis. Moreover, HK-II mRNA levels were significantly elevated in UUO renal tissues and in HK-2 cells stimulated with TGF-β1. Glycolytic inhibition effectively ameliorated tubular epithelial injury and fibrosis.
Conclusion: In this study, we identified a marked induction of tubular ATF4 in mice subjected to UUO. Silencing ATF4 significantly mitigated renal tubulointerstitial fibrosis. Mechanistically, ATF4 was shown to act as a key glycolytic driver by transcriptionally upregulating hexokinase II. Collectively, these findings indicate that tubular ATF4 facilitates renal tubulointerstitial fibrosis through HK-II mediated glycolytic activation.

Keywords: activating transcription factor 4; glycolysis; hexokinase II; kidney; tubulointerstitial fibrosis

DOI: https://doi.org/10.3389/fimmu.2025.1683249

World J Clin Oncol. 2025 Dec 24. 16(12): 114275

Inflammatory cytokine-associated cisplatin resistance in non-small cell lung cancer and re-sensitization through interleukin-6 receptor blockade.

Gizem Calibasi-Kocal.

Chemoresistance remains a major challenge in non-small cell lung cancer, especially for cisplatin (DDP)-based therapies, which are a mainstay of treatment. In their study, Dai et al investigate how inflammatory cytokines within the tumor microenvironment contribute to DDP resistance. By analyzing tumor samples from 20 non-small cell lung cancer patients and two resistant cell lines (A549/ DDP and SK-MES-1/DDP), the authors show that increased levels of interleukin (IL)-6, IL-8, and tumor necrosis factor-α are linked to resistance. Logistic regression identifies IL-6 and IL-8 as key risk factors. Functional experiments using tocilizumab, an IL-6 receptor antagonist, demonstrate a reduction in DDP half maximum inhibitory concentration, higher apoptosis rates, and decreased migration and invasion in resistant cells. Although the study has certain limitations, such as the analysis of only five inflammatory cytokines in a small, non-stratified patient cohort; it demonstrates that targeting the IL-6 cytokine axis may help overcome DDP resistance. Overall, the study highlights the inflammatory component of the tumor microenvironment as a modifiable driver of chemoresistance and provide a rationale for integrating cytokine blockade into platinum-based chemotherapy regimens to enhance therapeutic response.

Keywords: Cisplatin resistance; Cytokines; Interleukin-6; Non-small cell lung cancer; Tumor microenvironment

DOI: https://doi.org/10.5306/wjco.v16.i12.114275

Cell Metab. 2025 Dec 29. pii: S1550-4131(25)00530-3. [Epub ahead of print]

Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.

Jianbiao Xiao, Zhiyang Li, Yi Ding, Kejin Zhu, Zhihao Zheng, Yaowei Zhang, Jiawen Weng, Feifei Wang, Yuqin Zhang, Sisi Zeng, Minxing Qiu, Zhaowen Zhang, Zhizhang Wang, Li Liang.

Immune checkpoint blockade (ICB) faces limitations owing to high cost and restricted efficacy. This study identifies SNX17 as a key mediator of ICB resistance. Elevated SNX17 correlates with poor anti-PD-1 response in humans and mice. SNX17 deletion in tumor cells inhibits tumor growth via CD8+ T cell-dependent mechanisms. SNX17 reduces uridine in the tumor microenvironment (TME), suppressing IFN-γ and upregulating PD1 in CD8+ T cells. Exogenous uridine shows antitumor efficacy comparable to anti-PD-1/PD-L1 in low-SNX17 tumors and overcomes resistance in high-SNX17 models. Uridine enhances CD8+ T cell function by promoting CD45 N-glycosylation and LCK phosphorylation. Mechanistically, SNX17 stabilizes RUNX2, promoting UPP1 transcription and uridine degradation in the TME. These findings position SNX17 as an ICB response biomarker and nominate uridine as a cost-effective immunotherapeutic strategy.

Keywords: CD8+ T cell; N-glycosylation; SNX17; UPP1; checkpoint blockade; immunotherapy resistance; uridine

DOI: https://doi.org/10.1016/j.cmet.2025.11.016

Int J Mol Sci. 2025 Dec 17. pii: 12148. [Epub ahead of print]26(24):

Palmitic but Not Oleic Acid Induces Pro-Inflammatory Dysfunction of Human Endothelial Cells from Different Vascular Beds In Vitro.

Daria Shishkova, Victoria Markova, Yulia Yurieva, Alexey Frolov, Anastasia Lazebnaya, Maxim Sinitsky, Anna Sinitskaya, Vera Matveeva, Evgenia Torgunakova, Alexander Stepanov, Anna Malashicheva, Asker Khapchaev, Nikita Podkuychenko, Alexander Vorotnikov, Vladimir Shirinsky, Anton Kutikhin.

Palmitic acid (PA) is the most common dietary saturated fatty acid, and is abundant in palm and cottonseed oil, butter, and cheese, whereas oleic acid (OA) is a monounsaturated omega-9 fatty acid found in olive oil. The differences in the cytotoxic and pro-inflammatory effects of PA and OA across endothelial cells (ECs) isolated from different vascular beds have not been investigated in detail. Here, we incubated primary human aortic valve (HAVEC), saphenous vein (HSaVEC), internal thoracic artery (HITAEC), and microvascular (HMVEC) ECs with albumin-bound PA or OA for 24 h and found that PA induced a considerable cytotoxic response, accompanied by an elevated expression of the genes encoding cell adhesion molecules (VCAM1, ICAM1, SELE, and SELP) and pro-inflammatory cytokines (MIF, PTX3, CSF2, CSF3, IL1A, IL6, CCL2, CCL5, CCL20, CSF2, CSF3, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, and CXCL10), followed by an increased release of interleukin-6 and interleukin-8. HAVEC and HSaVEC were more susceptible to PA, whereas OA had mild-to-moderate cytotoxic effects on HAVEC and HMVEC but did not induce generalized EC activation. Compared with other EC types, HITAEC was the most resistant to PA and OA treatment. Collectively, these results indicate considerable heterogeneity across the ECs of distinct origin in response to PA.

Keywords: aortic valve; atherosclerosis; endothelial cells; endothelial dysfunction; internal thoracic artery; microvascular network; oleic acid; palmitic acid; saphenous vein; vascular inflammation

DOI: https://doi.org/10.3390/ijms262412148