bims-stacyt 2025-12-28 papers

Eur J Pharmacol. 2025 Dec 22. pii: S0014-2999(25)01259-2. [Epub ahead of print] 178505

GDF15 Attenuates Sepsis-Associated Liver Injury by Regulating Macrophage Polarization via the AMPK/PKM2/HIF-1a Pathway.

Li Wang, XianDong Kuang, Huan Li, Ye Zhang, Dongling Tang, ZhiLi Niu, Pingan Zhang.

Sepsis-associated liver injury (SALI) is a common and severe complication of sepsis, and effective clinical treatment strategies are still lacking. Macrophages, a highly heterogeneous population of immune cells, play a key role in triggering and regulating the cytokine storm. Enhanced glycolysis is the key driver behind the increased proportion of M1 macrophages and the elevated release of pro-inflammatory factors. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine with anti-inflammatory and tissue repair functions. However, the specific role and mechanism of GDF15 in SALI remain unclear. In this study, a mouse SALI model and a macrophage M1 polarization model were established using lipopolysaccharide (LPS). Recombinant GDF15 protein was used to investigate its role and related mechanisms. The results showed that GDF15 markedly alleviated liver injury and effectively suppressed the release of pro-inflammatory cytokines. In both in vivo and in vitro experiments, GDF15 promoted the polarization of macrophages from the M1 to the M2 phenotype. Mechanistically, GDF15 inhibits the pyruvate kinase M2 (PKM2)/ (hypoxia inducible factor 1α) HIF-1α axis-mediated glycolysis and macrophage M1 polarization by activating AMP-activated protein kinase (AMPK). These findings indicate that GDF15 is a potential target for the clinical prevention and treatment of SALI.

Keywords: AMPK; GDF15; HIF-1α; Macrophage polarization; PKM2; Sepsis-associated liver injury

DOI: https://doi.org/10.1016/j.ejphar.2025.178505

Signal Transduct Target Ther. 2025 Dec 24. 10(1): 417

Lipocalin-2 drives brain metastatic progression through reciprocal tumor-microenvironment interactions in lung cancer.

Yixiang Zhu, Jian Zhang, Danming He, Hongqing Cai, Yan He, Li Yuan, Sini Li, Yucheng Dong, Wei Zhuang, Zhijie Wang, Jianchun Duan, Xue Zhang, Zixiao Ma, Hua Bai, Jie Wang.

Brain metastasis is a major contributor to mortality in patients with lung cancer. The unique microenvironment of the brain plays a critical role in the initiation and progression of brain metastases (BM), yet the molecular mechanisms underlying tumor-microenvironment interactions remain poorly understood. Here, we demonstrate that upregulation of lipocalin-2 (LCN2) in tumor cells promotes brain metastatic progression by orchestrating crosstalk among metastatic tumor cells, astrocytes, and macrophages. Brain metastatic tumor cells secrete LCN2, which binds to SLC22A17 on astrocytes, activating JAK2/STAT3 signaling and inducing astrocyte activation and chemokine secretion, thereby facilitating macrophage recruitment. In turn, macrophages secrete IL-1β, which further upregulates LCN2 expression in tumor cells. Prophylactic administration of the IL-1 receptor antagonist anakinra inhibits BM formation, whereas therapeutic administration alone is ineffective. However, treatment with the STAT3 inhibitor SH4-54, either alone or in combination with anakinra, significantly suppressed tumor growth in the BM. Furthermore, tumor-secreted LCN2 can bind to SLC22A17 on tumor cells, activating JAK2/STAT3 signaling and promoting VEGF-A expression and release, which enhances tumor neovascularization. Inhibition of this axis with SH4-54, bevacizumab, or their combination effectively reduces the tumor burden in BM-bearing mice. These findings underscore the central role of LCN2 in driving brain metastasis and highlight a potential therapeutic strategy for targeting brain metastatic lung cancer.

DOI: https://doi.org/10.1038/s41392-025-02514-2

Nat Commun. 2025 Dec 23.

4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila.

Kristoffer Walsh, Hidetaka Katow, Hannah Junn, Deepika Vasudevan, Christoph Dieterich, Hyung Don Ryoo.

Cells adapt to proteostatic and metabolic stresses, in part, through stress activated eIF2α kinases that stimulate the translation of ATF4. Stress-induced ATF4 translation is regulated through elements at ATF4 mRNA's 5' leader. In addition to eIF2α kinases, ATF4 induction requires other regulators that remain poorly understood. Here, we report an ATF4 regulatory network consisting of eIF4E-Homologous Protein (4EHP), NELF-E, the 40S ribosome, and eIF3 subunits. Specifically, we found that the mRNA cap-binding protein, 4EHP, was required for ATF4 signaling in the Drosophila larval fat body and in disease models associated with abnormal ATF4 signaling. NELF-E mRNA, encoding a regulator of pol II-mediated transcription, was identified as a top interactor of 4EHP in a TRIBE (Targets of RNA Binding through Editing) screen. Quantitative proteomics analysis revealed that the knockdown of NELF-E or 4EHP commonly reduced several subunits of the 40S ribosome (RpS) and the eIF3 translation initiation factor. Moreover, reduction of NELF-E, 4EHP, RpS12, eIF3l, or eIF3h suppressed the expression of ATF4 and its target genes. These results uncover a previously unrecognized ATF4 regulatory network consisting of 4EHP and NELF-E that impacts proteostasis during normal development and in disease models.

DOI: https://doi.org/10.1038/s41467-025-67357-5

Exp Mol Med. 2025 Dec 25.

SLC6A14-mediated glutamine promotes SYTL4-CXCL8 axis activation to drive gemcitabine resistance and immune evasion in pancreatic cancer.

Hyeon Woong Kang, Ju Hyun Kim, Jae Woong Jeong, Sungsoon Fang, Won-Gun Yun, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park.

Chemoresistance remains a major challenge in pancreatic ductal adenocarcinoma (PDAC). Glutamine sustains drug resistance and shapes the immunosuppressive tumor microenvironment; however, the underlying mechanisms remain unclear. Identifying key regulators that drive both gemcitabine resistance and immune evasion is crucial for improving theapeutic outcomes in PDAC. Here we identified solute-carrier family 6 member 14 (SLC6A14) as the central regulator of glutamine metabolism that drives gemcitabine resistance. SLC6A14-mediated glutamine metabolism facilitated α-ketoglutarate production, activating mTOR/NF-κB signaling to upregulate PD-L1 expression, playing a central role in immune evasion. Moreover, SLC6A14 induced CXC motif chemokine ligand 8 secretion via synaptotagmin-like 4-mediated exocytosis, paracrinally activating CXCR2 signaling in cancer-associated fibroblasts to enhance mitochondrial fission and amino acid recycling, supporting PDAC progression. Targeting SLC6A14 with α-methyl-tryptophan enhanced gemcitabine sensitivity, suppressed PD-L1 driven immune evasion and reduced tumor growth, metastasis and glutamine production in vivo. These findings underscore SLC6A14 as a pivtoal mediator of glutamine-driven gemcitabine resistance and immune evasion in PDAC. Therapeutic strategies targeting SLC6A14, either alone or in combination with PD-L1 blockade, hold promise for overcoming chemoresistance and enhancing antitumor immunity in gemcitabine-resistant pancreatic cancer.

DOI: https://doi.org/10.1038/s12276-025-01596-w

J Nutr Sci. 2025 ;14 e84

Palmitic acid reduces cytosolic potassium and induces IL-1β production in lipopolysaccharide-primed human macrophages.

Jyue-Wei Chuang, Shao-Chun Lu.

Saturated fatty acids, particularly palmitic acid (PA), promote inflammation and contribute to chronic diseases such as type 2 diabetes and cardiovascular disease. PA induces interleukin-1 beta (IL-1β) production in lipopolysaccharide (LPS)-primed macrophages via NLRP3 inflammasome activation; but the underlying mechanism remains unclear. This study investigates whether PA-induced IL-1β production involves cytosolic potassium (K+) depletion. In LPS-primed macrophages, treatment with PA conjugated to bovine serum albumin (PA-BSA) significantly reduced cytosolic K+ levels and increased IL-1β production 2.4-fold. Stearic acid-BSA produced similar effects, whereas BSA-bound oleic, linoleic and docosahexaenoic acids had minimal impact. Voltage-gated potassium (Kv) channel blockers, 4-aminopyridine and tetraethylammonium chloride, attenuated PA-BSA-induced K+ efflux and IL-1β production in LPS-primed macrophages, implicating Kv channels as key mediators. These findings reveal a novel inflammatory pathway in which PA-BSA promotes IL-1β production via Kv channel-dependent K+ efflux, highlighting a mechanistic link between saturated fatty acid exposure and inflammatory signalling.

Keywords: interleukin-1 beta (IL-1β); macrophages; palmitic acid; potassium efflux; saturated fatty acids

DOI: https://doi.org/10.1017/jns.2025.10053