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Asiatic acid promotes CD8+ T cell-mediated antitumor immunity by targeting HDAC8/CXCL10 axis in hepatocellular carcinoma. 亚细亚酸通过靶向HDAC8/CXCL10轴在肝癌中促进CD8+ T细胞介导的抗肿瘤免疫
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-05 DOI: 10.1038/s41401-025-01739-9
Yu-Chuan Chen, Xue-Lian Gao, Ge Zeng, Kai-Kai Zhang, Chang Yuan, Chang-Hao Cheng, Jia-Yuan Wan, He-Qi Zhou, Zhi-Xian Lan, De-Kai Zheng, Qiu-Hong You, Jian Sun

Immunotherapy has shown limited efficacy in hepatocellular carcinoma (HCC) due to the immunosuppressive tumor microenvironment (TME). Previous studies show that asiatic acid (AA), a naturally occurring pentacyclic triterpenoid, exhibits potent inhibitory effects on tumor cell proliferation. In this study we investigated the effects of AA on the TME and immunotherapy in HCC. Both subcutaneous and orthotopic HCC models were established in male mice. The mice were treated with AA (50 mg·kg⁻¹·d⁻¹, i.g) for two weeks. At the experimental endpoint, mice were euthanized, and tumor-infiltrating immune cell populations were analyzed using flow cytometry. We showed that AA treatment effectively converted "cold tumors" into "hot tumors" by promoting CD8+ T cell infiltration and activation in HCC. We demonstrated that AA non-covalently bound and inhibited histone deacetylase 8 (HDAC8), increasing H3K27 acetylation at the CXCL10 promoter to enhance its expression. This epigenetic reprogramming elevated CXCL10 expression and drove robust CD8+ T cell recruitment. HDAC8 overexpression abolished these effects, confirming the target specificity. Importantly, we demonstrated that AA synergized with anti-PD-L1 therapy while maintaining a favorable safety profile. This study identifies AA as a novel HDAC8 inhibitor that remodels the TME, offering a promising strategy to overcome immunotherapy resistance in HCC.

由于免疫抑制肿瘤微环境(TME),免疫治疗对肝细胞癌(HCC)的疗效有限。先前的研究表明,asiatic acid (AA)是一种天然存在的五环三萜,对肿瘤细胞增殖具有有效的抑制作用。本研究探讨了AA对肝癌TME及免疫治疗的影响。在雄性小鼠中建立了皮下和原位肝癌模型。小鼠用AA (50 mg·kg⁻¹·d⁻,ig)治疗两周。在实验终点,小鼠被安乐死,用流式细胞术分析肿瘤浸润免疫细胞群。我们发现AA治疗通过促进CD8+ T细胞在HCC中的浸润和活化,有效地将“冷肿瘤”转化为“热肿瘤”。我们发现AA非共价结合并抑制组蛋白去乙酰化酶8 (HDAC8),增加CXCL10启动子上H3K27的乙酰化,从而增强其表达。这种表观遗传重编程提高了CXCL10的表达,并推动了CD8+ T细胞的强劲募集。HDAC8过表达消除了这些影响,证实了靶特异性。重要的是,我们证明了AA与抗pd - l1治疗协同作用,同时保持良好的安全性。本研究确定AA是一种新的HDAC8抑制剂,可以重塑TME,为克服HCC的免疫治疗耐药提供了一种有希望的策略。
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引用次数: 0
Epigenetic regulation and posttranslational modifications of FXR: underlying mechanisms and implications in digestive diseases. FXR的表观遗传调控和翻译后修饰:消化系统疾病的潜在机制和意义。
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-05 DOI: 10.1038/s41401-025-01726-0
Qian-Rui Mi, Cai-Qian Wu, Cheng-Guo Lv, Ke-Er Zhao, Zhao-Feng Liu, Peng-Fei Xu, Ling Li

The incidence of digestive system diseases is increasing, with liver diseases, obesity, inflammatory bowel disease (IBD), and hepatoenteric cancers being prominent contributors to global morbidity and mortality. Targeting farnesoid X receptor (FXR) has emerged as a promising therapeutic strategy for various digestive disorders. FXR is a member of the nuclear receptor superfamily, is expressed primarily in the liver and small intestine, and is activated by bile acids (BAs). Beyond classical ligand-dependent activation, FXR activity is precisely modulated by epigenetic regulation and posttranslational modifications (PTMs), such as DNA methylation, histone methylation and acetylation, noncoding RNA regulation, phosphorylation, acetylation, SUMOylation, ubiquitination, O-glycosylation, methylation, sulfhydration, and poly(ADP-ribosyl)ation. Growing evidence reveals disease-associated alterations in FXR modification patterns, offering novel therapeutic perspectives for digestive pathologies. In this review, we comprehensively summarize the structure of FXR, its regulatory mechanisms through epigenetic modifications and PTMs, and its potential application in the treatment of digestive diseases. The structure of FXR, its regulatory mechanisms through epigenetic modifications and PTMs, and its potential application in the treatment of digestive diseases. Upper: epigenetic regulation of FXR. Below: posttranslational modifications of FXR. OG O-glycosylation, P phosphorylation, SUMO SUMOylation, SSH sulfhydration, Ac acetylation, Me methylation, Ub ubiquitination.

消化系统疾病的发病率正在增加,肝病、肥胖、炎症性肠病(IBD)和肝癌是全球发病率和死亡率的主要原因。靶向法内甾体X受体(FXR)已成为一种有前景的治疗多种消化系统疾病的策略。FXR是核受体超家族的成员,主要在肝脏和小肠中表达,并被胆汁酸(BAs)激活。除了经典的配体依赖性激活外,FXR活性还受到表观遗传调控和翻译后修饰(PTMs)的精确调节,如DNA甲基化、组蛋白甲基化和乙酰化、非编码RNA调控、磷酸化、乙酰化、SUMOylation、泛素化、o -糖基化、甲基化、巯基化和聚(adp -核糖基)化。越来越多的证据揭示了FXR修饰模式的疾病相关改变,为消化疾病的治疗提供了新的视角。本文就FXR的结构、通过表观遗传修饰和PTMs的调控机制及其在消化系统疾病治疗中的潜在应用进行综述。FXR的结构,通过表观遗传修饰和PTMs的调控机制,及其在消化系统疾病治疗中的潜在应用。上图:FXR的表观遗传调控。下图为FXR的翻译后修饰。OG o糖基化,P磷酸化,SUMO SUMOylation, SSH巯基化,Ac乙酰化,Me甲基化,Ub泛素化。
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引用次数: 0
Molecular basis for cross-activation of NPFF2R by a short PrRP-related peptide. 短prrp相关肽交叉激活NPFF2R的分子基础。
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-04 DOI: 10.1038/s41401-025-01741-1
Xin Li, Shuai Li, Hong Shan, Qing-Ning Yuan, Xin-Heng He, Qian He, Min Zhang, Yang Li, Wen Hu, Kai Wu, H Eric Xu, Li-Hua Zhao

Prolactin-releasing peptide (PrRP) is an endogenous ligand for the PrRPR, whose activation has been linked to anti-obesity effects. However, PrRP and its analogs also activate the neuropeptide FF receptor 2 (NPFF2R), which is associated with adverse cardiovascular effects. Understanding how PrRP-related peptides differentially engage these two distinct receptors is critical for developing safer, more selective therapeutics. In this study, we present cryo-EM structures of the PrRP analog GUB08248 bound to PrRPR-Gαq and NPFF2R-Gαi at resolutions of 2.45 Å and 2.85 Å, respectively. These structures reveal a conserved ligand recognition mode across both receptors, while highlighting distinct receptor-specific interactions. The NPFF2R-Gαi complex further uncovers key features of receptor activation and G protein coupling. Together, our results offer structural insights that could guide structure-based drug design strategies favoring PrRPR selectivity, thereby advancing the therapeutic potential of the PrRP-PrRPR axis for obesity treatment.

催乳素释放肽(PrRP)是PrRPR的内源性配体,其激活与抗肥胖作用有关。然而,PrRP及其类似物也激活神经肽FF受体2 (NPFF2R),这与心血管不良反应有关。了解prrp相关肽如何不同地与这两种不同的受体结合,对于开发更安全、更有选择性的治疗方法至关重要。在这项研究中,我们获得了PrRP类似物GUB08248与prpr - g - αq和npff2r - g - αi结合的低温电镜结构,分辨率分别为2.45 Å和2.85 Å。这些结构揭示了两种受体之间保守的配体识别模式,同时突出了不同的受体特异性相互作用。NPFF2R-Gαi复合体进一步揭示了受体活化和G蛋白偶联的关键特征。总之,我们的研究结果提供了结构见解,可以指导基于结构的药物设计策略,有利于PrRPR选择性,从而提高PrRP-PrRPR轴在肥胖治疗中的治疗潜力。
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引用次数: 0
Oridonin exerts dual therapeutic effects in MASLD mice by integrating lipid homeostasis and drug bioactivation via the LXRα-CES1/CES2 pathway. Oridonin通过LXRα-CES1/CES2途径整合脂质稳态和药物生物活化,在MASLD小鼠中发挥双重治疗作用。
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-04 DOI: 10.1038/s41401-025-01737-x
Huan-Guo Jiang, Zhi-Kun Zhan, Ling-Min Tian, Yu-Lian Chen, Mei-Qun Cai, Guang-Bo Ge, Xin Chen, Chuan-Liang Wei, Lan Tang

Carboxylesterases CES1 and CES2 are the pivotal hepatic enzymes involved in triglyceride (TG) hydrolysis and prodrug metabolism, yet their expression and activity are suppressed in metabolic dysfunction-associated steatotic liver disease (MASLD). Liver X receptor alpha (LXRα) is known to play a crucial role in maintaining the constitutive expression of CES1 in human liver cells. Oridonin (ORI) is a diterpene derived from a traditional Chinese herb that possesses antitumor, anti-inflammatory, and antimicrobial activities. We previously demonstrated that ORI, as a natural LXRα agonist, activated the LXRα-ATGL/EPT1 pathway, correcting the TG/phosphatidylethanolamine (PE) lipid imbalance induced by obesity and thereby improving MASLD. Here, we investigated the regulatory role of LXRα on CES1/CES2 expression in MASLD liver and elucidated the underlying molecular mechanisms of ORI's lipid-lowering effects. A high-fat diet (HFD)-induced steatosis model was established in mice. The mice were treated with ORI (100 mg·kg-1·d-1, i.g.) from the 16th to the 24th week. RNA-seq analysis in MASLD patients demonstrated that LXRα is a key transcriptional regulator of CES1 and CES2. LXRα knockout (LXRα-/-) mice exhibited aggravated HFD-induced steatosis and impaired metabolic conversion of the CES1/CES2 substrates, oseltamivir and irinotecan. This deficiency resulted in a corresponding increase in their drug exposure (AUC) by 154.5% and 26.2%, respectively. Mechanistically, LXRα directly bound to liver X receptor response elements (LXREs) in the promoter regions of CES1 (-183/-165 bp) and CES2 (-1870/-1852 bp) to drive transcription in HepG2 cells. Furthermore, ORI (2.5, 5, 10 μM) dose-dependently restored CES1/CES2 expression and activity, reducing lipid accumulation. Silencing of CES1 or CES2 abolished ORI's lipid-lowering effect, confirming their essential roles. These findings establish the LXRα-CES1/CES2 pathway as a pivotal node integrating hepatic lipid homeostasis and drug metabolism, positioning ORI as a promising therapeutic agent for MASLD.

羧酸酯酶CES1和CES2是参与甘油三酯(TG)水解和前药代谢的关键肝酶,但它们的表达和活性在代谢功能障碍相关的脂肪变性肝病(MASLD)中受到抑制。已知肝X受体α (LXRα)在维持人肝细胞中CES1的组成性表达中起关键作用。oriidonin (ORI)是一种从传统中草药中提取的二萜,具有抗肿瘤、抗炎和抗菌活性。我们之前证明ORI作为一种天然的LXRα激动剂,激活LXRα- atgl /EPT1通路,纠正肥胖引起的TG/磷脂酰乙醇胺(PE)脂质失衡,从而改善MASLD。在此,我们研究了LXRα对MASLD肝脏中CES1/CES2表达的调控作用,并阐明了ORI降脂作用的潜在分子机制。建立小鼠高脂饮食诱导脂肪变性模型。小鼠于第16 ~ 24周ig ORI (100 mg·kg-1·d-1, ig)。对MASLD患者的RNA-seq分析表明,LXRα是CES1和CES2的关键转录调节因子。LXRα敲除(LXRα-/-)小鼠表现出hfd诱导的脂肪变性加重,CES1/CES2底物、奥司他韦和伊立替康代谢转化受损。这一缺陷导致他们的药物暴露(AUC)分别相应增加了154.5%和26.2%。在机制上,LXRα直接结合肝X受体反应元件(LXREs)在CES1 (-183/-165 bp)和CES2 (-1870/-1852 bp)的启动子区域驱动HepG2细胞的转录。此外,ORI(2.5、5、10 μM)剂量依赖性地恢复CES1/CES2的表达和活性,减少脂质积累。CES1或CES2的沉默消除了ORI的降脂作用,证实了它们的重要作用。这些发现证实LXRα-CES1/CES2通路是整合肝脏脂质稳态和药物代谢的关键节点,ORI有望成为治疗MASLD的药物。
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引用次数: 0
VsNsbench: evaluating AlphaFold3-embed induced-fit mechanism for enhanced virtual screening. VsNsbench:评估alphafold3嵌入诱导拟合机制增强虚拟筛选。
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-04 DOI: 10.1038/s41401-025-01732-2
Shu-Kai Gu, Chao Shen, Yu-Wei Yang, Si-Long Zhai, Jing Li, Ya-Nan Tian, Xu-Jun Zhang, Hong-Yan Du, Zhen-Xing Wu, Xiao-Rui Wang, Jing-Xuan Ge, Hui-Feng Zhao, Yuan-Sheng Huang, Gao-Qi Weng, Huan-Xiang Liu, Ting-Jun Hou, Yu Kang

While AlphaFold3 (AF3) extends AlphaFold2 (AF2) by predicting holo structures, it remains unclear whether its modeling process captures similar induced-fit mechanisms. In this study, we benchmarked the VS performance of ligand-induced AF3 holo structures on two datasets: a subset of DUD-E and VsNsBench designed to avoid sequence-level information leakage. On both datasets, AF3 holo structures demonstrated substantially improved enriching capability compared to AF3 apo, experimental apo, and AF2 structures. Compared to experimental holo structures, AF3 models demonstrated inferior performance on the DUD-E subset but performed slightly better on VsNsBench. Further analysis revealed that AF3's induced modeling critically depends on the bound ligand's affinity: high-affinity ligands produced conformations enabling excellent enrichment, while low-affinity or random ligands yielded poor performance. Moreover, direct VS using AF3 alone achieved satisfactory performance, but computational efficiency remains a major bottleneck for large-scale applications, even with single-round multiple sequence alignment (MSA) generation. In a DFG-motif kinase case study, AF3 successfully modeled inhibitor-specific conformations with a 75% success rate. These findings demonstrate that AF3 effectively incorporates induced-fit modeling, though improvement is needed, particularly for modeling multi-state conformational ensembles.

虽然AlphaFold3 (AF3)通过预测全息结构扩展了AlphaFold2 (AF2),但尚不清楚其建模过程是否捕获了类似的诱导拟合机制。在这项研究中,我们在两个数据集上对配体诱导的AF3全息结构的VS性能进行了基准测试:ddu - e和VsNsBench的一个子集,旨在避免序列级信息泄漏。在这两个数据集上,与AF3 apo、实验apo和AF2结构相比,AF3 holo结构的富集能力显著提高。与实验全息结构相比,AF3模型在ddu - e子集上的性能较差,但在VsNsBench上的性能略好。进一步分析表明,AF3的诱导建模严重依赖于结合配体的亲和力:高亲和力配体产生的构象能够实现良好的富集,而低亲和力或随机配体产生的构象性能较差。此外,单独使用AF3的直接VS取得了令人满意的性能,但计算效率仍然是大规模应用的主要瓶颈,即使是单轮多序列比对(MSA)生成。在dfg基序激酶案例研究中,AF3成功地以75%的成功率模拟了抑制剂特异性构象。这些发现表明,AF3有效地结合了诱导拟合模型,尽管还需要改进,特别是在建模多态构象集成方面。
{"title":"VsNsbench: evaluating AlphaFold3-embed induced-fit mechanism for enhanced virtual screening.","authors":"Shu-Kai Gu, Chao Shen, Yu-Wei Yang, Si-Long Zhai, Jing Li, Ya-Nan Tian, Xu-Jun Zhang, Hong-Yan Du, Zhen-Xing Wu, Xiao-Rui Wang, Jing-Xuan Ge, Hui-Feng Zhao, Yuan-Sheng Huang, Gao-Qi Weng, Huan-Xiang Liu, Ting-Jun Hou, Yu Kang","doi":"10.1038/s41401-025-01732-2","DOIUrl":"https://doi.org/10.1038/s41401-025-01732-2","url":null,"abstract":"<p><p>While AlphaFold3 (AF3) extends AlphaFold2 (AF2) by predicting holo structures, it remains unclear whether its modeling process captures similar induced-fit mechanisms. In this study, we benchmarked the VS performance of ligand-induced AF3 holo structures on two datasets: a subset of DUD-E and VsNsBench designed to avoid sequence-level information leakage. On both datasets, AF3 holo structures demonstrated substantially improved enriching capability compared to AF3 apo, experimental apo, and AF2 structures. Compared to experimental holo structures, AF3 models demonstrated inferior performance on the DUD-E subset but performed slightly better on VsNsBench. Further analysis revealed that AF3's induced modeling critically depends on the bound ligand's affinity: high-affinity ligands produced conformations enabling excellent enrichment, while low-affinity or random ligands yielded poor performance. Moreover, direct VS using AF3 alone achieved satisfactory performance, but computational efficiency remains a major bottleneck for large-scale applications, even with single-round multiple sequence alignment (MSA) generation. In a DFG-motif kinase case study, AF3 successfully modeled inhibitor-specific conformations with a 75% success rate. These findings demonstrate that AF3 effectively incorporates induced-fit modeling, though improvement is needed, particularly for modeling multi-state conformational ensembles.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Chronic 5-HT7R activation drives depressive phenotypes and synaptic dysfunction. 慢性5-HT7R激活驱动抑郁表型和突触功能障碍。
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-03 DOI: 10.1038/s41401-025-01722-4
Bartłomiej Pochwat, Julia Masternak, Bartosz Bobula, Krystian Bijata, Barbara Chruścicka-Smaga, Justyna Turek, Adam Hogendorf, Maria Walczak, Magdalena Smolik, Remigiusz Worch, Magdalena Kusek, Andrzej J Bojarski, Krzysztof Tokarski, Bernadeta Szewczyk, Monika Bijata

Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression, but their chronic use is associated with side effects and residual symptoms of depression. Both effects induced by SSRIs are mediated by serotonin receptor-dependent signaling pathways, yet the molecular mechanisms underlying these effects remain unclear. Here, we investigated the impact of chronic and acute activation of the 5-HT7 receptor (5-HT7R) using the selective agonist AGH-194 in male mice. Behavioral assessment revealed that chronic AGH-194 administration induced depressive-like effects in the novelty suppressed feeding test (NSFT), female urine sniffing test (FUST), and novel object location test (NOLT). After acute injection, depressive-like effects were observed only in NSFT. At the molecular level, AGH-194 administration activated matrix metalloproteinase 9 (MMP-9) through a 5-HT7R-Gαs signaling-dependent mechanism. Acute treatment induced transient activation, while chronic treatment led to prolonged enzymatic activity, accompanied by a reduction in the expression of the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in the hippocampus. At the cellular level, acute but not chronic AGH-194 treatment induced a shift toward more juvenile dendritic spine morphology in the CA1 and dentate gyrus (DG) regions of the hippocampus, along with an increase in dendritic spine density in DG. Electrophysiological recordings demonstrated that acute AGH-194 administration enhanced hippocampal excitability by increasing population spike amplitude in CA1. Chronic AGH-194 treatment further modulated short-term plasticity, increasing both population spike and extracellular field potential paired-pulse ratios (PS-PPR and EPSP-PPR) in CA1, while also enhancing the maximum EPSP slope amplitude. These findings provide novel evidence that chronic 5-HT7R activation can induce depressive-like behaviors in male mice, potentially through sustained MMP-9 activation and alterations in synaptic plasticity. Understanding the molecular and electrophysiological consequences of selective 5-HT7R stimulation may provide insights into receptor-specific mechanisms that could contribute to SSRI-induced side effects, thereby contributing to the development of improved antidepressant strategies.

选择性血清素再摄取抑制剂(SSRIs)通常用于治疗抑郁症,但其长期使用与副作用和抑郁症残留症状有关。SSRIs诱导的两种效应都是由血清素受体依赖的信号通路介导的,但这些效应的分子机制尚不清楚。在这里,我们研究了使用选择性激动剂AGH-194对雄性小鼠慢性和急性激活5-HT7受体(5-HT7R)的影响。行为评估显示,慢性AGH-194在新颖性抑制喂养试验(NSFT)、女性尿液嗅吸试验(FUST)和新物体定位试验(NOLT)中诱导抑郁样效应。急性注射后,仅在NSFT中观察到抑郁样作用。在分子水平上,AGH-194通过5- ht7r - g- αs信号依赖机制激活基质金属蛋白酶9 (MMP-9)。急性治疗诱导短暂激活,而慢性治疗导致酶活性延长,并伴有海马α-氨基-3-羟基-5-甲基-4-异氧唑丙酸受体(AMPAR)的GluA1亚基表达减少。在细胞水平上,急性而非慢性AGH-194治疗诱导海马CA1和齿状回(DG)区域向更年轻的树突棘形态转变,同时DG的树突棘密度增加。电生理记录显示,急性给药AGH-194通过增加CA1的群体峰幅来增强海马的兴奋性。慢性AGH-194处理进一步调节了短期可塑性,增加了CA1的群体峰值和细胞外场电位对脉冲比(PS-PPR和EPSP- ppr),同时增强了EPSP斜率的最大振幅。这些发现提供了新的证据,表明慢性5-HT7R激活可以诱导雄性小鼠的抑郁样行为,可能是通过持续的MMP-9激活和突触可塑性的改变。了解选择性5-HT7R刺激的分子和电生理后果可能有助于深入了解可能导致ssri诱导的副作用的受体特异性机制,从而有助于改进抗抑郁药物策略的发展。
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引用次数: 0
Discovery and characterization of a novel HIF-2α agonist for the treatment of CKD-related renal anemia. 一种治疗ckd相关肾性贫血的新型HIF-2α激动剂的发现和特性
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-01 Epub Date: 2025-10-01 DOI: 10.1038/s41401-025-01657-w
Shu-Qing Chu, Yi-Jie Chen, Rui-Rui Yang, Dan Teng, Gui-Zhen Zhou, Ying-Ying Zhang, Bu-Ying Niu, Jia-Hang Xu, Ke-Xin Lin, Xin-Yu Yang, Xu-Tong Li, Ming-Yue Zheng, Su-Lin Zhang

Hypoxia-inducible factor 2-alpha (HIF-2α), a critical transcription factor, forms a heterodimer with aryl hydrocarbon receptor nuclear translocator (ARNT) to drive the transcription of erythropoietin (EPO), a key regulator of erythropoiesis. Activation of this pathway plays a pivotal role in the treatment of anemia. By discovered structure-based virtual screening and pharmacological assays, we herein discovered an amide thiazole AT-1 that bound to HIF-2α with a KD of 2.63 μM, and enhanced the stability of the HIF-2α-ARNT heterodimer. Molecular docking and site-directed mutagenesis analysis revealed the critical roles of His293 and Tyr307 in the binding of AT-1 to HIF-2α. Pharmacological studies showed that AT-1 (10, 20, 40 μM) dose-dependently enhanced both the transcription and secretion of EPO in 786-O and Hep3B cells. In zebrafish (Danio rerio), AT-1 (10 or 50 μM) exhibited favorable safety profiles and, when combined with the prolyl hydroxylase (PHD) inhibitor Molidustat (10 μM), effectively mitigated doxorubicin-induced anemia. In adenine-induced chronic kidney disease (CKD) mouse model, combined administration of AT-1 (50 mg·kg-1·d-1, i.p.) and Molidustat (10 mg·kg-1·d-1, i.p.) for 15 days produced stronger effects on increasing EPO levels and alleviating anemia than Molidustat alone, further supporting the therapeutic potential of AT-1 in CKD-related anemia.

缺氧诱导因子2- α (HIF-2α)是一种关键的转录因子,与芳烃受体核转运子(ARNT)形成异二聚体,驱动促红细胞生成素(EPO)的转录,EPO是红细胞生成的关键调节因子。该通路的激活在贫血的治疗中起着关键作用。通过虚拟筛选和药理学实验,我们发现了一个与HIF-2α结合的氨基噻唑AT-1, KD为2.63 μM,增强了HIF-2α- arnt异源二聚体的稳定性。分子对接和定点诱变分析揭示了His293和Tyr307在AT-1与HIF-2α结合中的关键作用。药理研究表明,AT-1 (10,20,40 μM)剂量依赖性地促进了786-O和Hep3B细胞EPO的转录和分泌。在斑马鱼(Danio rerio)中,AT-1(10或50 μM)表现出良好的安全性,当与prolyl羟化酶(PHD)抑制剂Molidustat (10 μM)联合使用时,可有效减轻阿霉素诱导的贫血。在腺嘌呤诱导的慢性肾脏疾病(CKD)小鼠模型中,AT-1 (50 mg·kg-1·d-1, i.p)和莫里司他(10 mg·kg-1·d-1, i.p)联合用药15天,在增加EPO水平和减轻贫血方面的作用比莫里司他单独用药更强,进一步支持AT-1在CKD相关贫血中的治疗潜力。
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引用次数: 0
PXR ribosylation at E194 amplifies NAPQI in acetaminophen‒induced liver injury in mice, rescued by Schisandrin B. PXR核糖基化E194在五味子素B修复的对乙酰氨基酚诱导的小鼠肝损伤中扩增NAPQI。
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-01 Epub Date: 2025-10-01 DOI: 10.1038/s41401-025-01632-5
Jia-Chan Long, Chen-Xu Liu, Meng-Yao Wang, Cai-Hong Liu, Fan Zhang, Zhong-Qiu Liu, Lin An, Cai-Yan Wang

Acetaminophen (APAP)-induced acute liver injury (AILI) is primarily driven by CYP3A4‒mediated overproduction of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), CYP3A4 activity serves as the rate-limiting determinant of NAPQI accumulation levels. Poly ADP-ribose polymerase 1 (PARP1)-driven ribosylation, a posttranslational modification, has been linked to drug-induced liver injury. PARP1 interacts with pregnane X receptor (PXR), a nuclear receptor that regulates drug-metabolizing enzymes including CYP3A4. In this study we investigated the specific sites of PARP1-mediated PXR ribosylation, particularly regarding their functional relevance to CYP3A4-driven NAPQI biosynthesis in AILI. To establish AILI models, mice were injected with APAP (300 mg·kg-1, i.p.), liver tissues and serum were collected for analysis 24 h post-injection. In vitro study was conducted in primary hepatocytes isolated from AILI mice and in human hepatic L02 cells exposed to APAP (5, 10, 20 μM). We demonstrated that under AILI conditions, PARP1 catalyzed ribosylation of PXR at the residue E194, forming a PARP1-PXR‒CYP3A4 regulatory axis that amplified oxidative stress and NAPQI accumulation through a positive feedback loop. Specifically, PARP1 was significantly overexpressed in AILI models in vivo and in vitro, and its interaction with PXR was confirmed in immunoprecipitation and proximity biotinylation assays. Molecular dynamics (MD) simulations, mass spectrometry and E194A site-directed mutagenesis revealed that PARP1-mediated ribosylation of PXR E194 enhanced CYP3A4 transcription, ultimately leading to excessive NAPQI production. MD simulations also identified a natural compound schisandrin B (Sch B) that specifically bound to the ligand-binding domain of PXR, induced conformational changes and disrupted the PARP1-PXR interaction interface, thus suppressed the ribosylation. In AILI murine models, administration of Sch B (25, 50, and 100 mg·kg-1·d-1, i.g.) for 8 days significantly reduced serum ALT and AST levels, attenuated oxidative stress, and inhibited NAPQI generation by blocking complex formation. This study not only elucidates the mechanisms of PARP1-mediated PXR E194 ribosylation in AILI but also identifies Sch B as the first specific inhibitor of this pathway, providing a theoretical basis for precision detoxification strategies targeting posttranslational modifications.

对乙酰氨基酚(APAP)诱导的急性肝损伤(AILI)主要由CYP3A4介导的毒性代谢物n -乙酰基-对苯醌亚胺(NAPQI)的过量产生驱动,CYP3A4活性是NAPQI积累水平的限速决定因素。聚adp核糖聚合酶1 (PARP1)驱动的核糖基化是一种翻译后修饰,与药物性肝损伤有关。PARP1与孕烷X受体(PXR)相互作用,PXR是一种调节包括CYP3A4在内的药物代谢酶的核受体。在这项研究中,我们研究了parp1介导的PXR核糖基化的特定位点,特别是它们与AILI中cyp3a4驱动的NAPQI生物合成的功能相关性。采用APAP (300 mg·kg-1, ig)注射小鼠,24 h后采集肝组织和血清进行分析,建立AILI模型。体外实验分别在APAP(5、10、20 μM)作用下分离的AILI小鼠原代肝细胞和人肝L02细胞中进行。我们证明了在AILI条件下,PARP1在残基E194处催化PXR的核糖基化,形成PARP1-PXR - cyp3a4调节轴,通过正反馈回路放大氧化应激和NAPQI积累。具体来说,PARP1在体内和体外AILI模型中显著过表达,并且在免疫沉淀和邻近生物素化实验中证实了其与PXR的相互作用。分子动力学(MD)模拟、质谱分析和E194A位点定向突变显示,parp1介导的PXR E194核糖基化增强了CYP3A4的转录,最终导致NAPQI的过量产生。MD模拟还发现一种天然化合物schisandrin B (Sch B)特异性结合PXR的配体结合域,诱导构象变化,破坏PARP1-PXR相互作用界面,从而抑制核糖基化。在AILI小鼠模型中,连续8天给予Sch B(25、50和100 mg·kg-1·d-1, ig)可显著降低血清ALT和AST水平,减轻氧化应激,并通过阻断复合物的形成抑制NAPQI的生成。本研究不仅阐明了parp1介导的AILI中PXR E194核糖基化的机制,而且确定了Sch B是该途径的第一个特异性抑制剂,为针对翻译后修饰的精确解毒策略提供了理论基础。
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引用次数: 0
TNFSF15 alleviates myeloid-derived suppressor cell-mediated cancer immunosuppression in mice. TNFSF15减轻小鼠髓源性抑制细胞介导的癌症免疫抑制。
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-01 Epub Date: 2025-09-19 DOI: 10.1038/s41401-025-01663-y
Yi-Pan Zhu, Jing Sun, Xin-Yu Cao, Xin-Yu Ding, Yu-Ying Wang, Qiu-Ju Han, Jing-Ying Wang, Lu-Yuan Li, Zhi-Song Zhang

Myeloid-derived suppressor cells (MDSCs) are a category of immature myeloid cells that have an important function in suppressing immune responses in a variety of pathological settings. Thus, MDSCs are the subject of intensive studies regarding their recruitment, expulsion, deactivation, and maturation promotion. Tumor necrosis factor superfamily member 15 (TNFSF15) is produced largely by vascular endothelial cells in mature blood vessels with expression also observed in tumor-associated macrophages (TAMs) and dendritic cells (DCs) within the tumor stroma. In addition to inhibiting the proliferation of vascular endothelial cells and the differentiation of bone marrow-derived endothelial cell progenitors, TNFSF15 is able to promote the maturation of DC, as well as to modulate the polarization of naive M2-macrophages into M1-macrophages capable of eliminating cancer cells, and activate T-cell. In this study, we investigated whether a recombinant TNFSF15 results in a substantial reduction of MDSC accumulation in Lewis lung cancer (LLC) tumor-bearing mice. LLC allograft model mice were administered recombinant TNFSF15 (5 mg·kg-1·d-1, i.p.) for 7 consecutive days. The tumor, bone marrow and spleen were retrieved on Day 8 and analyzed using flow cytometry or immunofluorescence staining. We showed that TNFSF15 treatment significantly inhibited the tumor growth, and caused a substantial reduction of MDSC accumulation in the tumors. The proportions of MDSC in the bone marrows and the spleens were also reduced. The diminished MDSC was mainly the monocyte-like MDSC (M-MDSC) subtype. Additionally, the reduction in M-MDSC population was accompanied by an increase of the proportions of macrophages and DCs in the tumors. We demonstrated that TNFSF15 promoted M-MDSC differentiation by activating the JAK1/STAT3 signaling pathway. Moreover, the treatment gave rise to a markedly escalated accumulation of cytotoxic T cells in the tumors, attributing to tumor growth inhibition. Our results support the view that TNFSF15-driven differentiation of M-MDSC into DCs and macrophages, and the subsequent activation of T cells, may contribute partially to reinstitution of immunity in the tumor microenvironment.

髓源性抑制细胞(myeloid -derived suppressor cells, MDSCs)是一类未成熟的髓系细胞,在多种病理情况下具有抑制免疫应答的重要功能。因此,我们对MDSCs的募集、排出、失活和促进成熟进行了深入的研究。肿瘤坏死因子超家族成员15 (TNFSF15)主要由成熟血管中的血管内皮细胞产生,在肿瘤基质中的肿瘤相关巨噬细胞(tam)和树突状细胞(DCs)中也有表达。除了抑制血管内皮细胞的增殖和骨髓源性内皮细胞祖细胞的分化外,TNFSF15还能促进DC的成熟,并调节幼稚的m2 -巨噬细胞极化为能够消灭癌细胞的m1 -巨噬细胞,激活t细胞。在这项研究中,我们研究了重组TNFSF15是否能显著减少Lewis肺癌(LLC)荷瘤小鼠的MDSC积累。LLC同种异体移植模型小鼠连续7天给予重组TNFSF15 (5 mg·kg-1·d-1, ig)。第8天取肿瘤、骨髓和脾脏,用流式细胞术或免疫荧光染色进行分析。我们发现,TNFSF15治疗显著抑制肿瘤生长,并导致MDSC在肿瘤中的积累显著减少。骨髓和脾脏中MDSC的比例也降低。减少的MDSC主要是单核细胞样MDSC (M-MDSC)亚型。此外,M-MDSC群体的减少伴随着肿瘤中巨噬细胞和DCs比例的增加。我们证明TNFSF15通过激活JAK1/STAT3信号通路促进M-MDSC分化。此外,由于肿瘤生长抑制,治疗引起肿瘤中细胞毒性T细胞的显著积累。我们的研究结果支持这样的观点,即tnfsf15驱动M-MDSC向dc和巨噬细胞的分化,以及随后的T细胞激活,可能在一定程度上有助于肿瘤微环境中免疫的重建。
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引用次数: 0
Species differences in the hepatobiliary disposition of morphine-6-glucuronide mediated by hepatic transporters in rats and humans. 大鼠和人肝脏转运体介导的吗啡-6-葡萄糖醛酸盐肝胆配置的物种差异。
IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-01 Epub Date: 2025-09-15 DOI: 10.1038/s41401-025-01658-9
Zi-Tao Guo, Hong Wang, Ning-Jie Xie, Yu-Fan Zhou, Meng-Lin Zhang, Xin-Yao Kang, Jue Wang, Qing Zhu, Xiao-Yan Chen

Morphine-6-glucuronide (M6G), the active metabolite of morphine, is currently in clinical development due to its higher analgesic activity. In humans, intravenously administered M6G was predominantly eliminated unchanged through the kidney, whereas it was excreted into the urine as parent drug as well as its metabolites morphine and M3G in normal rats. In bile-duct-cannulated rats, however, bile excretion of the parent drug was the main route of clearance. In the study, we investigated the mechanisms underlying the species differences in vivo disposition of M6G. In hepatocyte uptake assay, we showed that M6G uptake in rat hepatocytes was 75-fold higher than that in human hepatocytes. Hepatic uptake transporter phenotyping study identified M6G as a substrate for rat rOatplal, rOatpla4, rOatp1b2, as well as for human hOATP1B1 and hOATP1B3. Among these, rOatps exhibited significantly stronger uptake of M6G compared to hOATPs. Furthermore, M6G was not a substrate for the canalicular efflux transporters MDR1, hBCRP/rBcrp, hBSEP/rBsep, and hMRP2, but it was recognized by rMrp2. These findings aligned with the observation that M6G exhibited significant biliary excretion in the rat sandwich cultured hepatocyte (SCH) model, but not in the human SCH. Additionally, no species differences were observed in renal uptake mediated by OAT3. Overall, M6G underwent renal clearance in humans via glomerular filtration and active secretion primarily mediated by hOAT3. Although a portion of M6G was also eliminated through the kidney in rats, the majority was subjected to enterohepatic circulation mediated primarily by rOatps and rMrp2, leading to the formation of morphine and M3G, which were subsequently excreted in the urine. The marked difference in the uptake activities of sinusoidal transporters hOATPs/rOatps and the substrate specificity of canalicular transporters hMRP2/rMrp2 were critical factors underlying the species differences in the hepatobiliary disposition of M6G.

吗啡-6-葡糖苷(吗啡-6-glucuronide, M6G)是吗啡的活性代谢物,具有较高的镇痛活性,目前正处于临床开发阶段。在人体中,静脉注射的M6G主要通过肾脏消除,而在正常大鼠中,它作为母体药物及其代谢产物吗啡和M3G排泄到尿液中。然而,在胆管插管大鼠中,母体药物的胆汁排泄是主要的清除途径。在这项研究中,我们研究了M6G体内分布的物种差异的机制。在肝细胞摄取实验中,我们发现大鼠肝细胞对M6G的摄取比人肝细胞高75倍。肝摄取转运体表型研究发现M6G是大鼠rOatplal、rOatpla4、rOatp1b2以及人hOATP1B1和hOATP1B3的底物。其中,与hoatp相比,roatp对M6G的吸收明显更强。此外,M6G不是小管外排转运体MDR1、hBCRP/rBcrp、hBSEP/rBsep和hMRP2的底物,但它被rMrp2识别。这些发现与M6G在大鼠夹层培养肝细胞(SCH)模型中表现出显著的胆道排泄,而在人SCH模型中则没有。此外,在OAT3介导的肾脏摄取中,没有观察到物种差异。总的来说,M6G在人体内主要通过hOAT3介导的肾小球滤过和活跃分泌进行肾脏清除。虽然一部分M6G也通过大鼠的肾脏排出,但大部分通过主要由roatp和rMrp2介导的肠肝循环,导致吗啡和M3G的形成,随后随尿液排出。窦状转运蛋白hoatp / roatp摄取活性的显著差异以及小管转运蛋白hMRP2/rMrp2的底物特异性是导致M6G在肝胆配置上的物种差异的关键因素。
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