Biochemical pharmacology最新文献_第10页

Targeting focal adhesion kinase (FAK) in non-small cell lung cancer (NSCLC): Molecular mechanisms and combination therapeutic strategies 靶向局灶黏附激酶（FAK）治疗非小细胞肺癌：分子机制和联合治疗策略。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-18 DOI: 10.1016/j.bcp.2026.117716

Yihua Zhang , Di Lu , Liying Zhang , Yuna Shao , Zhaowei Yan , Zeyi Liu

Owing to the lack of obvious early symptoms, most patients are diagnosed with non-small cell lung cancer (NSCLC) at advanced stages and miss the optimal window for surgical intervention, which limits treatment options. In recent years, with the advancement of research into the pathogenesis of NSCLC, numerous targeted inhibitors, such as those targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and mesenchymal epithelial transition factor (MET), have been developed for the treatment of NSCLC. Nevertheless, resistance to these agents has been observed to varying extents. An increasing number of studies have confirmed that focal adhesion kinase (FAK) has emerged as a key research focus because of its crucial role in NSCLC initiation, progression and resistance. Several FAK-targeted inhibitors have advanced into clinical evaluation; for example, CEP-37440 is undergoing phase I trials, whereas GSK-2256098 has reached phase II trials. However, the therapeutic efficacy of monotherapy remains suboptimal. Therefore, the combination of FAK inhibitors with other treatment modalities, such as chemotherapy, targeted therapy, and immunotherapy, has become a promising direction for research. An increasing body of preclinical evidence supports the notion that FAK inhibitors, when used in combination with other therapies, exhibit enhanced and reliable efficacy against NSCLC. This review summarizes the structure and functional characteristics of FAK, its role in the pathogenesis of NSCLC, the research progress on FAK inhibitors, and the current status and prospects of combining FAK inhibitors with other therapies for NSCLC. The aim is to provide new insights for future clinical trial design and combination therapy strategies for NSCLC.

由于缺乏明显的早期症状，大多数患者在晚期被诊断为非小细胞肺癌（NSCLC），错过了手术干预的最佳时机，这限制了治疗选择。近年来，随着对NSCLC发病机制研究的深入，许多靶向抑制剂被开发出来用于治疗NSCLC，如靶向表皮生长因子受体（EGFR）、间质淋巴瘤激酶（ALK）、间充质上皮过渡因子（MET）等。然而，已观察到对这些药物有不同程度的耐药性。越来越多的研究证实，局灶黏附激酶（focal adhesion kinase， FAK）在NSCLC的起始、进展和耐药过程中起着至关重要的作用，已成为一个重要的研究热点。一些FAK靶向抑制剂已经进入临床评估阶段；例如，CEP-37440正在进行I期试验，而GSK-2256098已进入II期试验。然而，单一疗法的治疗效果仍然不理想。因此，FAK抑制剂与化疗、靶向治疗、免疫治疗等其他治疗方式的联合治疗已成为一个很有前景的研究方向。越来越多的临床前证据支持FAK抑制剂与其他疗法联合使用时，对非小细胞肺癌表现出增强和可靠的疗效。本文就FAK的结构和功能特点、FAK在NSCLC发病中的作用、FAK抑制剂的研究进展以及FAK抑制剂联合其他治疗方法治疗NSCLC的现状和前景进行综述。目的是为未来非小细胞肺癌的临床试验设计和联合治疗策略提供新的见解。

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引用次数: 0

Silencing OGFOD1 ameliorates hepatic ischemia–reperfusion injury through abrogating oxidative stress and apoptosis via downregulating SPARC 沉默OGFOD1可通过下调SPARC来消除氧化应激和细胞凋亡，从而改善肝缺血再灌注损伤。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-18 DOI: 10.1016/j.bcp.2026.117719

Zexin Li , Xiao Wang , Yuanyuan Cui , Yi Liu , Rui Wei , Yixin Wang , Xiaolong Tang , Liangbin Li , Jiasai Li , Keqiang Zuo

Hepatic ischemia–reperfusion injury (HIRI) is a complicated pathological process impacting the prognosis of patients suffering from liver resection and transplantation surgery. 2-oxoglutarate and iron dependent oxygenase domain containing 1 (OGFOD1), a crucial factor involved in protein translation, was highly expressed during HIRI. However, its role as well as underlying mechanism is still unclear. In this study, two datasets from Gene Expression Omnibus database were analyzed and we focused on OGFOD1 which is associated with ischemia–reperfusion. Later, a HIRI rat model and a hypoxia/reoxygenation (H/R) hepatocyte model were established to explore the expression of OGFOD1 and its underlying mechanism. Furthermore, transcriptomics and proteomics were performed to analyze the downstreams of OGFOD1 in H/R hepatocytes. Our results showed that the expression of OGFOD1 in HIRI rats and H/R hepatocytes were higher than negative controls. OGFOD1 silencing ameliorated liver function, reduced hepatocellular apoptosis and mitigated oxidative stress. Later, the combined analysis of transcriptomics and proteomics showed that 5811 mRNAs and 476 proteins were modulated by OGFOD1 silencing and these factors were classified into four classes. Among these factors, secreted protein acidic and rich in cysteine (SPARC) in Class III, with decreased protein level but no-changed mRNA level, caught our eyes. Silencing OGFOD1 decreased the protein level of SPARC, but not its mRNA level. More interestingly, SPARC overexpression rescued the effects of OGFOD1 silencing on apoptosis and oxidative stress in H/R hepatocytes. Totally, OGFOD1 was a vital modulator during HIRI and its downregulation alleviated oxidative stress and apoptosis through declining SPARC protein level.

肝缺血再灌注损伤（HIRI）是影响肝切除移植术患者预后的复杂病理过程。2-氧戊二酸和铁依赖性加氧酶结构域1 （OGFOD1）是参与蛋白质翻译的关键因子，在HIRI期间高表达。然而，其作用和潜在机制尚不清楚。本研究分析了来自Gene Expression Omnibus数据库的两个数据集，我们重点研究了与缺血再灌注相关的OGFOD1。随后，建立HIRI大鼠模型和缺氧/再氧化（H/R）肝细胞模型，探讨OGFOD1的表达及其机制。此外，通过转录组学和蛋白质组学分析了H/R肝细胞中OGFOD1的下游。我们的结果显示，OGFOD1在HIRI大鼠和H/R肝细胞中的表达高于阴性对照组。OGFOD1沉默可改善肝功能，减少肝细胞凋亡，减轻氧化应激。随后，转录组学和蛋白质组学的联合分析表明，OGFOD1沉默可调节5811个mrna和476个蛋白，并将这些因子分为4类。其中，ⅲ类分泌蛋白呈酸性且富含半胱氨酸（SPARC），蛋白水平下降，但mRNA水平不变，引起了我们的注意。沉默OGFOD1可降低SPARC蛋白水平，但不影响其mRNA水平。更有趣的是，SPARC过表达挽救了OGFOD1沉默对H/R肝细胞凋亡和氧化应激的影响。综上所述，OGFOD1在HIRI中是一个重要的调节因子，其下调通过降低SPARC蛋白水平减轻氧化应激和细胞凋亡。

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引用次数: 0

Cajanolactone A alleviates high-fat diet-induced MAFLD by modulating liver de novo lipogenesis, inflammatory signaling, and bile acid composition in the gut-liver axis 菜籽内酯A通过调节肝脏新生脂肪生成、炎症信号和肠-肝轴胆汁酸组成来减轻高脂肪饮食诱导的MAFLD。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.bcp.2026.117717

Zaibin Xu , Kongyan Wang , Xiaoqin Wu , Tingting Chen , Like Xu , Yi Qiu , Huiyu Hu , Yan Chen , Jiazhong Cai , Yingjie Hu , Jiawen Huang , Zhuohui Luo

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease worldwide, affecting more than a quarter of the adult population. Cajanolactone A (CLA), a stilbenoid derived from Cajanus cajan, has been shown to significantly reduce hepatic lipid accumulation. However, its molecular mechanisms in MAFLD remain unclear. In this high-fat diet (HFD)-induced mice model of MAFLD, CLA significantly improved dyslipidemia, suppressed liver de novo lipogenesis by downregulating the expression of core genes and proteins involved in glycolysis and the tricarboxylic acid (TCA) cycle, and regulated SREBP-1c/ChREBP signaling to improve lipid metabolism and maintain lipid homeostasis. Furthermore, CLA markedly ameliorated the TLR4/NF-κB p65 signaling-mediated inflammatory microenvironment induced by HFD-stimulated intestinal endotoxins, increased the expression of intestinal tight junction (TJ) biomarkers Claudin-1 and ZO-1, protected intestinal barrier permeability, and enhanced intestinal immune function homeostasis, inhibited NF-κB p65/NLRP3-mediated inflammatory cascades in the liver by suppressing gut-liver axis signaling, activated liver FXR to regulate bile acid (BA) composition, thereby alleviating MAFLD. Overall, these findings suggest that CLA reduces HFD-induced MAFLD by regulating de novo lipogenesis, lipolysis, inflammatory signaling, and BA composition in the gut-liver axis, laying a scientific foundation for clinical prevention and treatment of MAFLD.

代谢功能障碍相关脂肪肝（MAFLD）是世界范围内常见的慢性肝病，影响超过四分之一的成年人口。Cajanolactone A (CLA)，一种从Cajanus cajan中提取的二苯乙烯类化合物，已被证明可以显著减少肝脏脂质积累。然而，其在MAFLD中的分子机制尚不清楚。在高脂饮食（HFD）诱导的mald小鼠模型中，CLA显著改善血脂异常，通过下调糖酵解和三羧酸（TCA）循环相关核心基因和蛋白的表达，抑制肝脏新生脂肪生成，调节SREBP-1c/ChREBP信号，改善脂质代谢，维持脂质稳态。此外，CLA可显著改善hfd刺激肠道内毒素诱导的TLR4/NF-κB p65信号介导的炎症微环境，增加肠道紧密连接（TJ）生物标志物cladin -1和ZO-1的表达，保护肠道屏障通透性，增强肠道免疫功能稳态，通过抑制肠-肝轴信号传导抑制NF-κB p65/ nlrp3介导的肝脏炎症级联反应。激活肝脏FXR调节胆汁酸（BA）组成，从而缓解MAFLD。综上所述，CLA通过调节肝脏-肠轴的新生脂肪生成、脂肪分解、炎症信号和BA组成，降低了hfd诱导的MAFLD，为临床预防和治疗MAFLD奠定了科学基础。

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引用次数: 0

Entinostat suppresses hepatocellular carcinoma metastasis by upregulating AZGP1 through histone acetylation 恩替司他通过组蛋白乙酰化上调AZGP1抑制肝癌转移。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.bcp.2026.117718

Weiguo Cai , Xinru Pei , Xiaodie Ye , Yan Zhai , Na Wu , Ziyi Wang , Wei Lu

Hepatocellular carcinoma (HCC) has a high mortality rate, primarily driven by metastasis. The role of the histone deacetylase inhibitor (HDACi) entinostat in this process remains controversial, limiting its clinical application. This study aims to define entinostat’s function and mechanism in HCC metastasis. We employed in vitro models, transcriptomic sequencing, chromatin immunoprecipitation-qPCR, and an orthotopic mouse model to assess the effects of entinostat on epithelial-mesenchymal transition (EMT), invasion, and tumor growth. Our findings demonstrate that entinostat potently prevented and reversed transforming growth factor-β (TGF-β)-induced EMT, suppressing HCC cell invasion and metastasis in vivo without significant toxicity. Transcriptomics identified alpha-2-glycoprotein 1, zinc-binding (AZGP1) as a key target. In addition, entinostat promotes histone H4 acetylation at the AZGP1 promoter, activating its transcription. AZGP1 overexpression mimicked entinostat’s effects, while its knockdown largely abolished them. Clinically, high AZGP1 expression was associated with an improved prognosis. In conclusion, our work elucidates a coherent epigenetic pathway wherein entinostat activates AZGP1 to inhibit HCC metastasis. These findings nominate AZGP1 as both a critical mediator and a potential biomarker for entinostat-based therapy in advanced HCC.

肝细胞癌（HCC）的死亡率很高，主要是由转移引起的。组蛋白去乙酰化酶抑制剂（HDACi）恩替司他在这一过程中的作用仍然存在争议，限制了其临床应用。本研究旨在明确恩替司他在HCC转移中的作用及机制。我们采用体外模型、转录组测序、染色质免疫沉淀- qpcr和原位小鼠模型来评估entinostat对上皮-间质转化（EMT）、侵袭和肿瘤生长的影响。我们的研究结果表明，恩替司他能有效地预防和逆转转化生长因子-β (TGF-β)诱导的EMT，在体内抑制HCC细胞的侵袭和转移，而没有明显的毒性。转录组学鉴定α -2-糖蛋白1，锌结合（AZGP1）为关键靶点。此外，entinostat促进AZGP1启动子上的组蛋白H4乙酰化，激活其转录。AZGP1过表达模仿了entinostat的作用，而它的敲除在很大程度上消除了它们。临床上，AZGP1高表达与预后改善相关。总之，我们的工作阐明了一种连贯的表观遗传途径，其中恩替诺他激活AZGP1以抑制HCC转移。这些发现表明AZGP1是晚期HCC依替诺他汀治疗的关键介质和潜在生物标志物。

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引用次数: 0

Metabolic activation of lumisterol to biologically active metabolites and their mechanism of action lumisterol对生物活性代谢物的代谢活化及其作用机制。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.bcp.2026.117711

Andrzej T. Slominski , Tae-Kang Kim , Zorica Janjetovic , Senthilkumar Ravichandran , Yuwei Song , Ewa Podgorska , Radomir M. Slominski , Franz Ewendt , Yuhua Song , Justyna Szpotan , Alisa A. Mobley , Cynthia J. Schwartz , Vyshnavi Rallapalle , Arup K. Indra , David K. Crossman , Michael B. Fessler , Anton M. Jetten , Michael F. Holick , Robert C. Tuckey

Lumisterol₃ (L₃) is produced photochemically from 7-dehydrocholesterol (7-DHC) in response to high doses of ultraviolet B (UVB). We previously demonstrated that it can be hydroxylated to mono- and dihydroxy-lumisterols by CYP11A1 and CYP27A1. In the present study, we demonstrate the presence of CYP27A1-derived 25(OH)L₃, (25R)-27(OH)L₃ and (25S)-27(OH)L₃ in the epidermis and human serum. Human immortalized epidermal keratinocytes and human colonic Caco-2 and murine hepatoma (Hepa 1–6) metabolized L₃ to these biologically active hydroxyderivatives. These metabolites stimulated keratinocyte differentiation and inhibited keratinocyte proliferation. We also demonstrate that L₃ and L₃-hydroxymetabolites protect human epidermal melanocytes against UVB irradiation by inhibiting reactive oxygen species production and DNA damage. Addition of 20S(OH)L₃ to murine dermal fibroblasts induced significant changes in their gene expression profiles that were different from those induced by structurally related 20S(OH)cholesterol, 20S(OH)7-DHC and 20S(OH)D₃. The L₃ hydroxymetabolites interacted with the aryl hydrocarbon receptor (AhR) and the peroxisome proliferator-activated receptor γ (PPARγ), as demonstrated in functional assays and molecular modeling. These findings indicate that these hydroxylumisterols can regulate biological functions of epidermal cells by acting on AhR and PPARγ. Thus, L₃ generated in the skin by UVB radiation can act as a pro-hormone that is metabolized intracellularly by CYP11A1 and CYP27A1 into biologically active metabolites. These metabolites can regulate skin functions, and possibly have other biological functions after they enter the systemic circulation. These findings open previously unexpected, exciting new areas of research on the physiological role of lumisterols through their action on defined nuclear receptors.

Lumisterol3 （L3）是由7-脱氢胆固醇（7-DHC）在高剂量紫外线B （UVB）下光化学反应产生的。我们之前已经证明它可以被CYP11A1和CYP27A1羟基化成单羟基和二羟基lumisterol。在本研究中，我们证实了cyp27a1衍生的25(OH)L3、(25R)-27(OH)L3和(25S)-27(OH)L3存在于表皮和人血清中。人永生化表皮角质形成细胞和人结肠Caco-2和小鼠肝癌（Hepa 1-6）将L3代谢为这些具有生物活性的羟基衍生物。这些代谢物刺激角质细胞分化，抑制角质细胞增殖。我们还证明L3和L3-羟基代谢物通过抑制活性氧的产生和DNA损伤来保护人类表皮黑色素细胞免受UVB照射。小鼠真皮成纤维细胞添加20S(OH)L3后，其基因表达谱发生了显著变化，与结构相关的20S（OH）胆固醇、20S(OH)7-DHC和20S(OH)D3诱导的基因表达谱不同。L3羟基代谢物与芳烃受体（AhR）和过氧化物酶体增殖激活受体γ (PPARγ)相互作用，在功能分析和分子模型中得到证实。这些结果表明，这些羟基茴香醇可能通过作用于AhR和PPARγ来调节表皮细胞的生物学功能。因此，UVB辐射在皮肤中产生的L3可以作为促激素，在细胞内被CYP11A1和CYP27A1代谢为具有生物活性的代谢物。这些代谢物可以调节皮肤功能，进入体循环后可能具有其他生物学功能。这些发现打开了以前意想不到的、令人兴奋的新研究领域，通过对特定核受体的作用来研究lumisterol的生理作用。

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引用次数: 0

Repurposing dronedarone for colorectal cancer therapeutic via suppression of the AKT/ERK signaling pathways 通过抑制AKT/ERK信号通路，将drone - edarone用于结直肠癌治疗。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-16 DOI: 10.1016/j.bcp.2026.117715

Tong Gong , Yan Jin , Hongmei Zhu , Zeying Cheng , Hong Fang , Ning Xu , Fanting Zhao , Yingqian Liu , Peng Chen

Colorectal cancer (CRC) remains one of the most prevalent and challenging cancers and advanced CRCs are resistant to targeted therapy, chemotherapy and immunotherapy. Therefore, it is urgent to develop new treatment strategies or therapeutic agents for CRC to improve clinical efficacy. Within the landscape of emerging therapeutic modalities, drug repurposing offers a particularly promising avenue for enhancing clinical outcomes. Herein, we revealed the functional repurposing of dronedarone, an FDA (the US Food and Drug Administration)-approved class III antiarrhythmic agent, demonstrating its potent anti-proliferative effects against CRC cells. Through rational drug structure modification, we synthesized thirteen dronedarone derivatives, among which derivative D4 demonstrated superior antiproliferative potency and lower toxicity both in vitro and in vivo. Mechanically, dronedarone and D4 induced mitochondrial dysfunction and suppressed both AKT (protein kinase B) and ERK (extracellular regulated protein kinase) signaling pathways simultaneously leading to CRC cells apoptosis. Collectively, our study sheds light on repurposing non-oncology drug dronedarone and its derivatives with their molecular mechanisms for CRC treatment.

结直肠癌（CRC）仍然是最普遍和最具挑战性的癌症之一，晚期结直肠癌对靶向治疗、化疗和免疫治疗具有耐药性。因此，迫切需要开发新的治疗策略或药物来提高结直肠癌的临床疗效。在新兴的治疗模式中，药物再利用为提高临床结果提供了一个特别有希望的途径。在此，我们揭示了dronedarone的功能改造，FDA（美国食品和药物管理局）批准的III类抗心律失常药物，显示其对CRC细胞的有效抗增殖作用。通过合理的药物结构修饰，我们合成了13个drone - edarone衍生物，其中衍生物D4在体外和体内均表现出较强的抗增殖能力和较低的毒性。机械上，dronedarone和D4诱导线粒体功能障碍，同时抑制AKT（蛋白激酶B）和ERK（细胞外调节蛋白激酶）信号通路，导致结直肠癌细胞凋亡。总的来说，我们的研究揭示了非肿瘤药物drone - edarone及其衍生物在CRC治疗中的分子机制。

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引用次数: 0

Arachidonic acid analog AACOCF3 suppresses cPLA2-negative NSCLC cell proliferation by targeting SSRP1 to activate the IFNα/β pathway 花生四烯酸类似物AACOCF3通过靶向SSRP1激活IFNα/β通路抑制cpla2阴性NSCLC细胞增殖。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117708

Hongbo Wang , Zihao Wen , Yupeng Jia , Xinyu Tong , Weifang Wang , Ze Wang , Hongkai Jin , Xiaoya Gao , Xinyuan Tao , Hao Cheng , Tingting Li , Shinan Li , Tingting Chen , Kunfang Li , Bo Li

AACOCF3, a cell-permeable arachidonic acid analogue, is widely established as a selective inhibitor of cytosolic phospholipase A2 (cPLA2, PLA2G4A) in studies of metabolic disorders. Although its primary mechanism involves cPLA2 inhibition, emerging evidence indicates that AACOCF3 may target additional protein entities, exemplified by calcium-independent phospholipase A2 (iPLA2, PLA2G6) and fatty acid amide hydrolase (FAAH). Notably, cPLA2 displays a markedly heterogeneous expression profile in non-small cell lung cancer (NSCLC). Our findings establish that AACOCF3 exerts more potent growth inhibition in cPLA2-negative NSCLC cells, with IC50 values of 15.13 μM for H1975 and 15.84 μM for PC9 cells, in contrast to the cPLA2-positive A549 cells (IC50 = 56.23 μM). Mechanistically, AACOCF3 upregulates IFN-α/β signaling-associated genes (e.g., IFNB1, ISG15) specifically in cPLA2-negative NSCLC cells. This aligns with TCGA-LUAD data revealing that PLA2G4A-low tumors predominantly engage immune-activation pathways rather than metabolic programs when compared to PLA2G4A-high counterparts. Through integrated molecular docking and surface plasmon resonance (SPR) analysis, we identified structure-specific recognition protein 1 (SSRP1) as a direct molecular target of AACOCF3 in cPLA2-negative NSCLC, with SPR binding studies confirming a stable interaction (Kd = 25.9 μM). Ectopic SSRP1 expression abrogated AACOCF3-induced phenotypic alterations, concurrently suppressing IFN-α/β signaling. Collectively, these results provide evidence that AACOCF3 exerts its anti-proliferative effect by targeting SSRP1, which leads to the activation of the IFNα/β pathway, thereby underscoring its therapeutic promise for the cPLA2-negative patient subpopulation.

AACOCF3是一种具有细胞渗透性的花生四烯酸类似物，在代谢紊乱的研究中被广泛认为是胞质磷脂酶A2 （cPLA2, PLA2G4A）的选择性抑制剂。尽管其主要机制涉及cPLA2抑制，但新出现的证据表明，AACOCF3可能靶向其他蛋白质实体，例如钙非依赖性磷脂酶A2 （iPLA2, PLA2G6）和脂肪酸酰胺水解酶（FAAH）。值得注意的是，cPLA2在非小细胞肺癌（NSCLC）中表现出明显的异质性表达谱。研究结果表明，与cpla2阳性的A549细胞（IC50 = 56.23 μM）相比，AACOCF3在cpla2阴性的NSCLC细胞中具有更强的生长抑制作用，H1975细胞的IC50值为15.13 μM， PC9细胞的IC50值为15.84 μM。在机制上，AACOCF3在cpla2阴性的NSCLC细胞中特异性上调IFN-α/β信号相关基因（如IFNB1， ISG15）。这与TCGA-LUAD数据一致，表明与pla2g4a高水平的肿瘤相比，pla2g4a低水平的肿瘤主要参与免疫激活途径而不是代谢程序。通过综合分子对接和表面等离子体共振（SPR）分析，我们确定了结构特异性识别蛋白1 （SSRP1）是AACOCF3在cpla2阴性NSCLC中的直接分子靶点，SPR结合研究证实了稳定的相互作用（Kd = 25.9 μM）。异位SSRP1表达消除了aacocf3诱导的表型改变，同时抑制了IFN-α/β信号传导。总之，这些结果证明AACOCF3通过靶向SSRP1发挥其抗增殖作用，从而导致IFNα/β通路的激活，从而强调了其治疗cpla2阴性患者亚群的前景。

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引用次数: 0

Onecut2, negatively regulated by methyltransferase METTL3, inhibits polycystic ovary syndrome by transcriptionally modulating SIRT3 expression Onecut2受甲基转移酶METTL3负调控，通过转录调节SIRT3表达抑制多囊卵巢综合征。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117712

Mingxing Sui, Shuying Wu, Qingqing Song, Siyao Chen, Yingli Lu

Polycystic ovary syndrome (PCOS) is characterized by a constellation of symptoms, including menstrual cycle irregularities, hyperandrogenism, and polycystic ovarian morphology. Despite extensive research efforts, a thorough understanding of the underlying pathophysiology and effective treatment options for PCOS remain elusive. In this study, ovarian tissues from dehydroepiandrosterone (DHEA)-induced PCOS mice and control mice underwent mRNA sequencing. Through a comprehensive bioinformatics analysis, we systematically examined the sequencing data, and one cut homeobox 2 (Onecut2), a significantly downregulated gene in PCOS mice, was identified and selected as the primary research target. Our findings determined that the overexpression of Onecut2 efficiently alleviated pathological changes and reduced mitochondrial dysfunction in DHEA-induced PCOS mice. Additionally, Onecut2 was found to be expressed at a low level in human ovarian granulosa KGN cells treated with dihydrotestosterone (DHT). Gain-of-function and loss-of-function experiments uncovered that Onecut2 played a role in inhibiting apoptosis and mitochondrial damage in DHT-treated KGN cells. Dual-luciferase reporter assays demonstrated that Onecut2 overexpression activated the transcriptional activity of the sirtuin 3 (SIRT3) promoter, thereby controlling the function of granulosa cells. Mechanistic investigation revealed that the mRNA stability of Onecut2 was regulated by methyltransferase-like 3 (METTL3) via m6A modification. Collectively, this study demonstrates that Onecut2 exerts an inhibitory role in PCOS progression by transcriptionally regulating SIRT3 expression and that this regulation is influenced by METTL3-mediated m6A methylation.

多囊卵巢综合征（PCOS）以一系列症状为特征，包括月经周期不规则、雄激素过多和多囊卵巢形态。尽管进行了广泛的研究，但对多囊卵巢综合征的潜在病理生理和有效治疗方案的透彻理解仍然难以捉摸。在本研究中，对脱氢表雄酮（DHEA）诱导的PCOS小鼠和对照小鼠的卵巢组织进行mRNA测序。通过全面的生物信息学分析，我们系统地检查了测序数据，确定并选择了PCOS小鼠中显著下调的一个剪切同源盒2 （Onecut2）基因作为主要研究目标。我们的研究结果表明，Onecut2的过表达有效地缓解了dhea诱导的PCOS小鼠的病理变化，并减少了线粒体功能障碍。此外，Onecut2被发现在双氢睾酮（DHT）处理的人卵巢颗粒KGN细胞中低水平表达。功能获得和功能丧失实验发现，Onecut2在dht处理的KGN细胞中发挥抑制凋亡和线粒体损伤的作用。双荧光素酶报告基因分析表明，Onecut2过表达激活sirtuin 3 （SIRT3）启动子的转录活性，从而控制颗粒细胞的功能。机制研究表明，Onecut2的mRNA稳定性受甲基转移酶样3 （METTL3）通过m6A修饰调控。综上所述，本研究表明Onecut2通过转录调节SIRT3表达在PCOS进展中发挥抑制作用，而这种调节受mettl3介导的m6A甲基化的影响。

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引用次数: 0

Corrigendum to “Almonertinib inhibits liver cancer progression by triggering autophagy-dependent ferroptosis through inhibition of the PI3K/Akt1/mTOR pathway”. [Biochem. Pharmacol. 245 (2026) 117628] “Almonertinib通过抑制PI3K/Akt1/mTOR通路触发自噬依赖性铁下垂来抑制肝癌进展”的更正。(生物化学。药理学杂志。245 (2026)117628 [j]

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117690

Lulu Liang , Xueshuang Wang , Baier Sun , Yipeng Sun , Jing Chen , Jiebang Jiang , Li Meng , Sisi He , Rongpeng Li , Fei Wang

引用次数: 0

Mertk-driven tunneling nanotube formation in macrophages preserves mitochondrial homeostasis during kidney Ischemia-Reperfusion Attack 巨噬细胞中mertk驱动的隧道纳米管形成在肾缺血再灌注攻击期间保持线粒体稳态。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117713

Jun Zeng , Ruoqing Li , Liyin Chai , Ying Zhang , Li Gong , Xiaolin Yuan , Qiufang Bai , Shuping Xiao , Jialian Wang , Sha Xiang , Haili Sun , Zhengyang Liu , Xingqing Chen , Ning Li , Bailin Niu , Mei Mei , Bingbing Shen

Renal ischemia–reperfusion (I/R) injury is a critical pathological process in organ transplantation and acute kidney injury (AKI), involving oxidative stress, inflammation, and mitochondrial dysfunction. Macrophage-expressed Mertk, a key regulator of tissue homeostasis, remains understudied in renal I/R injury. Mertk knockout (Mertk-KO) mice and their wild-type (WT) littermates were subjected to renal I/R injury. Mertk deficiency exacerbated renal tubular injury, inflammation, and oxidative stress in I/R-induced AKI. ATP production decreased, and mitochondrial morphology was disrupted in RTECs from Mertk-KO mice compared to WT mice. In vitro studies demonstrated that knockdown of Mertk in kidney-resident macrophages (KRMs) aggravated renal tubular epithelial cells (RTECs) injury, proliferation inhibition, apoptosis, and mitochondrial dysfunction under hypoxia-reoxygenation (H/R) conditions. Conversely, Mertk overexpression in KRMs attenuated these detrimental effects. Notably, Mertk overexpression facilitated tunneling nanotubes (TNTs) formation and promoted intercellular mitochondrial trafficking between KRMs and RTECs, maintaining mitochondrial homeostasis in RTECs. LAT-A treatment inhibited TNTs formation and abrogated the protective effects of Mertk overexpression. This study established Mertk as a critical mediator of KRMs-RTECs crosstalk through TNTs-dependent mitochondrial homeostasis regulation, providing mechanistic insights into AKI progression. Mertk-expressed KRMs-mediated mitochondrial transfer through TNT formation, providing a potential therapeutic target for AKI.

肾缺血再灌注（I/R）损伤是器官移植和急性肾损伤（AKI）的重要病理过程，涉及氧化应激、炎症和线粒体功能障碍。巨噬细胞表达的Mertk是组织稳态的关键调节因子，在肾I/R损伤中的研究尚不充分。Mertk敲除（Mertk- ko）小鼠及其野生型（WT）仔鼠遭受肾I/R损伤。在I/ r诱导的AKI中，Mertk缺乏加重了肾小管损伤、炎症和氧化应激。与WT小鼠相比，Mertk-KO小鼠RTECs中ATP的产生减少，线粒体形态被破坏。体外研究表明，在缺氧-再氧（H/R）条件下，肾内巨噬细胞（KRMs）中Mertk的敲低会加重肾小管上皮细胞（RTECs）损伤、增殖抑制、凋亡和线粒体功能障碍。相反，KRMs中Mertk的过表达减轻了这些有害影响。值得注意的是，Mertk过表达促进了隧道纳米管（TNTs）的形成，促进了KRMs和rtec之间的细胞间线粒体运输，维持了rtec中的线粒体稳态。lata处理抑制了TNTs的形成，并消除了Mertk过表达的保护作用。本研究证实Mertk是通过依赖tnts的线粒体稳态调节介导KRMs-RTECs串扰的关键介质，为AKI进展提供了机制上的深入了解。mertk表达的krms通过TNT形成介导的线粒体转移，为AKI提供了潜在的治疗靶点。

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