bims-meprid 2025-04-13 papers

Nat Commun. 2025 Apr 04. 16(1): 3230

Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.

Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.

DOI: https://doi.org/10.1038/s41467-025-58563-2

Sci Adv. 2025 Apr 11. 11(15): eads3506

Asparagine transporter supports macrophage inflammation via histone phosphorylation.

Chuanlong Wang, Yuyi Ye, Muyang Zhao, Qingyi Chen, Bingnan Liu, Wenkai Ren.

Solute carrier (SLC) family is essential for immune responses; nevertheless, whether and how SLCs regulate macrophage inflammation remains unclear. Here, we demonstrate that K636 acetylation mediates high abundance of SLC6A14 in inflammatory macrophages. Notably, the pharmacological inhibition or genetic modulation of SLC6A14 reduces macrophage interleukin-1β (IL-1β) secretion dependently of lower asparagine uptake and subsequently enhanced nuclear LKB1. Mechanistically, nuclear LKB1 lessens MAPK pathway-mediated NLRP3 inflammasome activation by increased histone 3 S10/28 phosphorylation-dependent cyclin O transcription. Moreover, myeloid Slc6a14 deficiency alleviates pulmonary inflammation via suppressing inflammatory macrophage responses. Overall, these results uncover a network by which SLC6A14-mediated asparagine uptake orchestrates macrophage inflammation through histone phosphorylation, providing a crucial target for modulation of inflammatory diseases.

DOI: https://doi.org/10.1126/sciadv.ads3506

Gut Microbes. 2025 Dec;17(1): 2489070

Fusobacterium nucleatum exacerbates colitis via STAT3 activation induced by Acetyl-CoA accumulation.

Zixuan Xiang, Xiangyun Li, Xiaoli Wang, Beiying Deng, Haodong He, Miao Xu, Xiaohan Wu, Cheng Tan, Yafei Liu, Baoping Yu, Jixiang Zhang, Weiguo Dong.

Fusobacterium nucleatum (F. nucleatum) has emerged as a potential contributor to ulcerative colitis (UC) pathogenesis, although the specific mechanisms remain incompletely understood. This study demonstrates that F. nucleatum promotes colitis by disrupting intestinal barrier integrity, inducing apoptosis in epithelial cells, and modulating inflammatory pathways. Furthermore, we demonstrate that F. nucleatum promotes STAT3 acetylation at K685, followed by phosphorylation at Y705, thereby enhancing its transcriptional activity and exacerbating colitis severity. Additionally, F. nucleatum-mediated upregulation of acetyl-CoA levels is responsible for STAT3 acetylation, linking metabolic processes to UC pathophysiology. Pharmacological inhibition of acetyl-CoA production effectively mitigates F. nucleatum-induced colitis in experimental models, suggesting potential therapeutic strategies targeting these pathways. These findings unveil a novel regulatory pathway in F. nucleatum-associated UC progression and offer new insights for future UC prevention and treatment.

Keywords: Acetyl-CoA; Fusobacterium nucleatum; STAT3; acetylation; ulcerative colitis

DOI: https://doi.org/10.1080/19490976.2025.2489070

J Immunol. 2025 Apr 09. pii: vkaf034. [Epub ahead of print]

Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.

Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These T cell subsets rely on distinct metabolic programs, modulation of which differentially affects T cell fate and function. Lipid metabolism is fundamental yet remains poorly understood across CD4+ T cell subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid metabolism genes and pathways essential for T cell functions. These screens established mitochondrial fatty acid synthesis genes Mecr, Mcat, and Oxsm as key metabolic regulators. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Mecrfl/fl; Cd4cre mice had normal naïve CD4+ and CD8+ T cell numbers, demonstrating that MECR is not essential in homeostatic conditions. However, effector and memory T cells were reduced in Mecr knockout and MECR-deficient CD4+ T cells and proliferated, differentiated, and survived less well than control T cells. Interestingly, T cells ultimately showed signs of mitochondrial stress and dysfunction in the absence of MECR. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced tricarboxylic acid intermediates, and accumulated intracellular iron, which appeared to contribute to increased cell death and sensitivity to ferroptosis. Importantly, MECR-deficient T cells exhibited fitness disadvantages and were less effective at driving disease in an in vivo model of inflammatory bowel disease. Thus, MECR-mediated metabolism broadly supports CD4+ T cell proliferation and survival in vivo. These findings may also provide insight to the immunological state of MECR- and other mitochondrial fatty acid synthesis-deficient patients.

Keywords: CD4+ T cells; MECR; lipid metabolism; mtFAS

DOI: https://doi.org/10.1093/jimmun/vkaf034

Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2423991122

Nat10-mediated N4-acetylcytidine modification enhances Nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis.

Xiaoyi Mo, Keyu Meng, Bohan Xu, Zehui Li, Shanwei Lan, Zhengda Ren, Xin Xiang, Peiqian Zou, Zesen Chen, Zhongming Lai, Xiang Ao, Zhongyuan Liu, Wanjing Shang, Bingyang Dai, Li Luo, Jiajia Xu, Zhizhang Wang, Zhongmin Zhang.

Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4-acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency (TE) of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.

Keywords: N4‐acetylcytidine; Nat10; Nfatc1; osteoporosis

DOI: https://doi.org/10.1073/pnas.2423991122