Biochemical pharmacology最新文献_第9页

tRF-Gly-CCC-012 enhances malignant process in pancreatic cancer via the HNRNPC/PHGDH axis tRF-Gly-CCC-012通过HNRNPC/PHGDH轴增强胰腺癌的恶性过程

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-20 DOI: 10.1016/j.bcp.2026.117726

Xiaohong Li , Yue Pan , Luolin Zhou , Lei Qi , Jingjing Lu

Pancreatic cancer (PC) is a devastating disease with rising incidence and mortality rates, characterized by late-stage presentation and aggressive progression, underscoring the urgent need for effective therapies. Recent studies have highlighted tRNA-derived fragments (tRFs) as potential therapeutic targets and biomarkers in cancer. In this study, we identified the cancer-associated tRF, tRF-Gly-CCC-012, which was observed to be highly expressed in PC tissues and cell lines. FISH and Nuclear/cytoplasmic RNA isolation analyses showed that tRF-Gly-CCC-012 was predominantly localized in the cytoplasm. Knockdown of tRF-Gly-CCC-012 suppressed aggressive phenotypes in PC cells, whereas its overexpression conversely promoted malignancy in PC organoids. In vivo experiments further confirmed that inhibition of tRF-Gly-CCC-012 suppressed PC cell growth. Mechanistically, RNA sequencing analysis demonstrated that tRF-Gly-CCC-012 upregulated the expression of PHGDH, involved in serine synthesis. RNA pulldown assays combined with mass spectrometry (MS) showed that tRF-Gly-CCC-012 specifically bound to the 162–306 amino acid domain of HNRNPC. Furthermore, tRF-Gly-CCC-012 enhanced HNRNPC protein expression by inhibiting its ubiquitination and degradation, leading to an upregulation of PHGDH and promoting the malignant progression of PC. These findings highlight tRF-Gly-CCC-012 as a viable diagnostic biomarker for PC, providing insights for detection and innovative strategies for clinical intervention.

胰腺癌（PC）是一种发病率和死亡率不断上升的毁灭性疾病，其特点是晚期出现和侵袭性进展，迫切需要有效的治疗方法。最近的研究强调了trna衍生片段（tRFs）作为癌症潜在的治疗靶点和生物标志物。在这项研究中，我们发现了与癌症相关的tRF， tRF- gly - cc -012，在PC组织和细胞系中被观察到高表达。FISH和核/细胞质RNA分离分析表明，trf - gly - cc -012主要定位于细胞质中。trf - gly - cc -012的敲低抑制了PC细胞的侵袭性表型，而其过表达则反过来促进了PC类器官的恶性肿瘤。体内实验进一步证实，抑制trf - gly - cc -012可抑制PC细胞生长。机制上，RNA测序分析表明，trf - gly - cc -012上调了参与丝氨酸合成的PHGDH的表达。RNA拉下分析结合质谱分析表明，trf - gly - cc -012特异性结合HNRNPC的162-306个氨基酸结构域。此外，trf - gly - cc -012通过抑制HNRNPC蛋白的泛素化和降解，增强HNRNPC蛋白的表达，导致PHGDH上调，促进PC的恶性进展。这些发现强调了trf - gly - cc -012作为一种可行的PC诊断生物标志物，为临床干预的检测和创新策略提供了见解。

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引用次数: 0

Carbamazepine disrupts the hypothalamic-pituitary-testicular axis and induces hormonal imbalances and sperm damage through activating GABBR2 to inhibit AC/cAMP/PKA pathway 卡马西平通过激活GABBR2抑制AC/cAMP/PKA通路，破坏下丘脑-垂体-睾丸轴，引起激素失衡和精子损伤

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-20 DOI: 10.1016/j.bcp.2026.117722

Jingya Li , Ziao Liu , Min Pan , Jing Xu , Xiaohan Ni , Kun Zhang , Tongsheng Wang , Li Li

Carbamazepine (CBZ), a widely prescribed antiepileptic drug, is known to cause male reproductive toxicity, yet the underlying biological pathways remain poorly characterized. This study comprehensively investigated the impact of CBZ on the hypothalamic-pituitary–testicular (HPT) axis using integrated in vivo and in vitro models to decipher the precise molecular mechanisms involved. Rats subjected to long-term exposure (12 weeks) to CBZ at doses of 100, 200, and 400 mg/kg showed structural damage in the hypothalamus, pituitary, and testes. Concurrently, serum levels of gonadotropin-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were reduced, indicating impairment of the HPT axis function. In-depth mechanistic studies demonstrated that CBZ suppressed the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway by upregulating the expression of gamma-aminobutyric acid type B receptor subunit 2 (GABBR2) protein, thereby triggering apoptosis of hypothalamic GnRH neurons. When GABBR2 was knocked down in GT1-7 cells (an immortalized mouse hypothalamic GnRH neuronal cell line), the AC/cAMP/PKA inhibition induced by CBZ was significantly attenuated, apoptosis was reduced, and GnRH secretion was partially restored. These findings indicate that activation of GABBR2, by repressing the AC/cAMP/PKA pathway, plays a pivotal role in CBZ-induced apoptosis of hypothalamic neurons, reduction of GnRH levels, and disruption of the HPT axis. This provides a new perspective for understanding CBZ-induced male reproductive toxicity.

卡马西平（CBZ）是一种广泛使用的抗癫痫药物，已知会导致男性生殖毒性，但其潜在的生物学途径仍不清楚。本研究通过综合体内和体外模型，全面研究了CBZ对下丘脑-垂体-睾丸（HPT）轴的影响，以破译其中的精确分子机制。大鼠长期暴露于100、200和400 mg/kg剂量的CBZ（12周）后，下丘脑、垂体和睾丸出现结构性损伤。同时，血清促性腺激素释放激素（GnRH）、促卵泡激素（FSH）、促黄体生成素（LH）和睾酮水平降低，提示HPT轴功能受损。深入的机制研究表明，CBZ通过上调γ -氨基丁酸B型受体亚基2 （GABBR2）蛋白的表达，抑制腺苷酸环化酶(AC)/环磷酸腺苷(cAMP)/蛋白激酶A （PKA）信号通路，从而引发下丘脑GnRH神经元凋亡。GT1-7细胞（小鼠下丘脑GnRH神经元系）敲除GABBR2后，CBZ诱导的AC/cAMP/PKA抑制明显减弱，细胞凋亡减少，GnRH分泌部分恢复。这些发现表明，GABBR2的激活，通过抑制AC/cAMP/PKA通路，在cbz诱导的下丘脑神经元凋亡、GnRH水平降低和HPT轴破坏中起关键作用。这为认识cbz诱导的男性生殖毒性提供了新的视角。

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引用次数: 0

Neurophysiological and neuropharmacological effects of melatonin MT2 receptors activation in MK-801-induced schizophrenia-like dysfunctions 褪黑激素MT2受体激活在mk -801诱导的精神分裂症样功能障碍中的神经生理和神经药理作用。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-20 DOI: 10.1016/j.bcp.2026.117725

Benedetta Barzon , Federica Marchiotto , Sofia Nasini , Antonino Casile , Sabina Peluso , Carlo Cifani , Nikolaos Pitsikas , Gabriella Gobbi , Marco Cambiaghi , Stefano Comai

Schizophrenia (SCZ) is a chronic psychiatric disorder characterized by positive, negative, and cognitive symptoms that remain insufficiently controlled by current dopamine- and serotonin-based antipsychotics. Emerging evidence implicates melatonin MT2 receptors in the regulation of the sleep-wake cycle, circadian rhythms and cortical inhibition, both altered in SCZ. Here, we investigated the neuropharmacological effects of the selective MT2 partial agonist UCM924 in the MK-801 model of SCZ-like dysfunctions in male mice. UCM924 (10 mg/kg, intraperitoneally) was selected as a dose not affecting basal locomotion. Acute administration of MK-801 (0.3 mg/kg) induced hyperlocomotion, social interaction abnormalities, and impaired spatial working memory. UCM924 normalized MK-801-induced hyperactivity and social deficits but did not improve cognitive performance. Immunofluorescence analysis revealed that UCM924 increased c-Fos activation in parvalbumin-positive interneurons of the prefrontal cortex, with no effect on tyrosine hydroxylase-positive neurons in the ventral tegmental area. Local field potential recordings showed that UCM924 alone reduced gamma-band power (12–90 Hz) in both regions, whereas MK-801 markedly enhanced it. Co-administration of MK-801 and UCM924 resulted in MK-801-dominant oscillatory patterns, suggesting limited efficacy of MT2 activation in restoring network synchronization. These findings indicate that MT2 receptor stimulation selectively enhances prefrontal inhibitory tone and ameliorates behavioral abnormalities related to positive-like and negative-like symptoms, without normalizing cognitive and electrophysiological deficits. Overall, MT2 receptor-selective drugs may represent promising candidates for targeting specific symptom domains in SCZ through mechanisms distinct from current antipsychotics.

精神分裂症（SCZ）是一种以阳性、阴性和认知症状为特征的慢性精神疾病，目前以多巴胺和血清素为基础的抗精神病药物仍不能充分控制这些症状。新出现的证据表明褪黑激素MT2受体参与调节睡眠-觉醒周期、昼夜节律和皮质抑制，这两者在SCZ中都发生了改变。在这里，我们研究了选择性MT2部分激动剂UCM924在MK-801雄性小鼠scz样功能障碍模型中的神经药理学作用。选择UCM924（10 mg/kg，腹腔注射）作为不影响基础运动的剂量。急性给药MK-801（0.3 mg/kg）会导致运动过度、社会互动异常和空间工作记忆受损。UCM924使mk -801诱导的多动和社交缺陷正常化，但没有改善认知表现。免疫荧光分析显示，UCM924增加了前额叶皮层小蛋白阳性中间神经元中c-Fos的激活，而对腹侧被盖区酪氨酸羟化酶阳性神经元没有影响。局部场电位记录显示，UCM924单独降低了两个区域的γ波段功率（12-90 Hz），而MK-801显著增强了它。同时给药MK-801和UCM924导致MK-801主导的振荡模式，表明MT2激活在恢复网络同步方面的作用有限。这些发现表明，MT2受体刺激选择性地增强前额叶抑制性张力，改善与阳性样和阴性样症状相关的行为异常，而不会使认知和电生理缺陷正常化。总的来说，MT2受体选择性药物可能通过不同于当前抗精神病药物的机制，代表了针对SCZ特定症状域的有希望的候选者。

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引用次数: 0

Structural and molecular characterization of a small-molecule TNF-α–TNFR1 inhibitor modulating cell death signaling 调节细胞死亡信号的小分子TNF -α-TNFR1抑制剂的结构和分子表征

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-20 DOI: 10.1016/j.bcp.2026.117727

Hana Seo , Muhammad Haseeb , Sangdun Choi

Tumor necrosis factor alpha (TNF-α) is a central mediator of inflammation and autoimmunity, where dysregulated activation of apoptotic and necroptotic pathways drives progressive tissue damage. Although monoclonal antibody therapies against TNF-α have provided clinical benefit, limitations related to parenteral delivery, immunogenicity, and incomplete suppression of downstream signaling underscore the need for alternative therapeutic approaches. Despite the pivotal role of TNF-α in chronic inflammation, no small-molecule inhibitor has yet reached clinical approval, with only a few candidates currently under clinical investigation. Here, we report the identification and mechanistic characterization of TI-16, a novel small-molecule inhibitor of TNF-α–TNFR1 interaction, discovered through structure-based virtual screening and validated by biophysical and cellular assays. TI-16 effectively protected fibroblasts from TNF-α–induced apoptosis and necroptosis and reduced the release of proinflammatory cytokines. Mechanistic analyses using immunoblotting, surface plasmon resonance, and molecular dynamics simulations demonstrated that TI-16 selectively disrupts tumor necrosis factor-alpha/tumor necrosis factor receptor 1 (TNF-α/TNFR1) interaction without altering TNF-α trimerization. By simultaneously suppressing apoptotic and necroptotic signaling, TI-16 overcomes key limitations of current biologics and represents a promising lead for the development of a novel class of orally available TNF-α–targeted therapeutics.

肿瘤坏死因子α (TNF-α)是炎症和自身免疫的中心介质，其中凋亡和坏死途径的失调激活驱动进行性组织损伤。尽管针对TNF-α的单克隆抗体治疗提供了临床益处，但与肠外给药、免疫原性和下游信号不完全抑制相关的局限性强调了替代治疗方法的必要性。尽管TNF-α在慢性炎症中起着关键作用，但尚未有小分子抑制剂获得临床批准，目前只有少数候选药物正在临床研究中。在这里，我们报告了TI-16的鉴定和机制表征，TI-16是一种新型的TNF -α-TNFR1相互作用的小分子抑制剂，通过基于结构的虚拟筛选发现并通过生物物理和细胞试验验证。TI-16能有效保护成纤维细胞免受TNF-α -诱导的凋亡和坏死下垂，减少促炎细胞因子的释放。利用免疫印迹、表面等离子体共振和分子动力学模拟的机制分析表明，TI-16选择性地破坏肿瘤坏死因子-α/肿瘤坏死因子受体1 （TNF-α/TNFR1）的相互作用，而不改变TNF-α三聚体化。通过同时抑制凋亡和坏死信号传导，TI-16克服了当前生物制剂的关键局限性，并代表了一种新型口服TNF-α -靶向治疗药物的发展前景。

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引用次数: 0

Macrophage migration inhibitory factor superfamily in tumor metabolism: mechanistic insights and therapeutic potential 巨噬细胞迁移抑制因子超家族在肿瘤代谢中的作用：机制见解和治疗潜力。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-18 DOI: 10.1016/j.bcp.2026.117720

Wenli Xie , Yanlei Dong , Jiao Lv , Xiangyu Wang

Macrophage migration inhibitory factor (MIF) is a versatile cytokine that links inflammation to tumor metabolism. It signals through CD74, along with co-receptors C-X-C chemokine receptor 2, 4, and 7 (CXCR2/CXCR4/CXCR7), activating the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and extracellular signal-regulated kinase (ERK) pathways. MIF also engages the mechanistic target of rapamycin complex 1 (mTORC1)/activating transcription factor 4 (ATF4) module to reprogram metabolic processes. This review explains how MIF promotes glucose uptake and aerobic glycolysis (the Warburg effect) and coordinates lipid regulators—sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs)—to enhance lipid uptake, de novo lipogenesis, acyl-chain remodeling, β-oxidation flexibility, and cholesterol/membrane homeostasis. It also reshapes amino acid transport, glutamine utilization, redox balance, and sensitivity to ferroptosis. The focus is on receptor-specific entry points, module-level outcomes, and how the tumor microenvironment affects nutrient competition and immune suppression. To avoid over-interpretation, evidence is graded by strength: [1] direct target engagement with pathway pharmacodynamics; [2] pathway-level signals alone; and [3] scaffold-level plausibility. Validation uses a standard set of assays, including orthogonal biophysical methods, receptor-proximal pharmacodynamic readouts, and isotope-tracing flux measurements. The review critically assesses current small-molecule classes targeting the catalytic pocket or trimer/interface to identify design principles for next-generation, receptor-focused modulators suitable for combination therapy. Finally, it proposes an imaging- and flux-based translational approach to select patients, confirm on-target action, and rationally pair MIF-axis blockade with metabolic or immunotherapeutic strategies—aiming to transform correlative data into mechanism-based clinical trials.

巨噬细胞迁移抑制因子（MIF）是一种连接炎症和肿瘤代谢的多功能细胞因子。它通过CD74和共受体C-X-C趋化因子受体2,4和7 （CXCR2/CXCR4/CXCR7）发出信号，激活磷酸肌苷3-激酶/蛋白激酶B （PI3K/AKT）和细胞外信号调节激酶（ERK）途径。MIF还参与雷帕霉素复合物1 (mTORC1)/激活转录因子4 （ATF4）模块的机制靶点，以重编程代谢过程。这篇综述解释了MIF如何促进葡萄糖摄取和有氧糖酵解（Warburg效应），并协调脂质调节剂——固醇调节元件结合蛋白（SREBPs）和过氧化物酶体增殖激活受体（ppar）——以增强脂质摄取、新生脂肪生成、酰基链重塑、β-氧化柔韧性和胆固醇/膜稳态。它还重塑氨基酸运输、谷氨酰胺利用、氧化还原平衡和对铁下垂的敏感性。重点是受体特异性进入点，模块水平的结果，以及肿瘤微环境如何影响营养竞争和免疫抑制。为了避免过度解释，证据按强度分级：[1]直接靶点参与途径药效学；[2]通路电平信号；和[3]脚手架级的合理性。验证使用一套标准的测定方法，包括正交生物物理方法、受体近端药效学读数和同位素示踪通量测量。该综述批判性地评估了目前针对催化口袋或三聚体/界面的小分子类，以确定适合联合治疗的下一代受体聚焦调节剂的设计原则。最后，该研究提出了一种基于成像和通量的转化方法，以选择患者，确认靶标作用，并将mif轴阻断与代谢或免疫治疗策略合理配对，旨在将相关数据转化为基于机制的临床试验。

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引用次数: 0

Targeted degradation of CD24 by a transferrin receptor-engaging bispecific degrader enhances antitumor immunity 通过转铁蛋白受体参与的双特异性降解物靶向降解CD24增强抗肿瘤免疫。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-18 DOI: 10.1016/j.bcp.2026.117721

Maorong Zhu , Yuxin Wu , Kuo Zhang , Lei He , Huihui Ou , Zhengcong Cao , Xiao Liu , Cheng Zou , Guangzhao Yang , Haozhe Qin , Dan Zheng , Duo Yu , Wangqian Zhang , Shuning Wang , Yingqi Zhang , Meng Li , Yalong He , Jintao Gu

Targeted degradation of extracellular and membrane-associated proteins has emerged as a promising therapeutic modality. Here, we developed CD24-H7, a novel bispecific degrader that engages the transferrin receptor (TFRC) to mediate lysosomal degradation of CD24—an immunosuppressive protein commonly overexpressed in tumors. CD24-H7 consists of a TFRC-binding scFv and a CD24-specific scFv linked by a cathepsin-cleavable spacer, facilitating efficient internalization, lysosomal delivery, and subsequent recycling of TFRC. In vitro and in vivo experiments revealed potent and specific degradation of CD24, leading to marked suppression of tumor growth and enhanced antitumor immunity in humanized mouse glioblastoma (GBM) models. The degrader also exhibited a favorable safety profile with minimal on-target off-tumor toxicity. Moreover, combining CD24-H7 with anti–PD-1 antibodies synergistically promoted intratumoral CD8⁺ T cell infiltration and cytotoxicity while attenuating T cell exhaustion, resulting in significantly enhanced antitumor efficacy compared to monotherapy. These findings underscore the therapeutic potential of TFRC-recruiting degraders for selective targeting of membrane proteins and provide a compelling combinatorial approach to overcome immune evasion in oncology.

靶向降解细胞外和膜相关蛋白已成为一种有前途的治疗方式。在这里，我们开发了CD24-H7，一种新的双特异性降解物，与转铁蛋白受体（TFRC）结合，介导cd24的溶酶体降解，cd24是肿瘤中常见的过度表达的免疫抑制蛋白。CD24-H7由一个结合TFRC的scFv和一个由组织蛋白酶可切割间隔连接的cd24特异性scFv组成，促进有效的内化、溶酶体递送和随后的TFRC回收。体外和体内实验显示，CD24的有效和特异性降解，导致人源化小鼠胶质母细胞瘤（GBM）模型的肿瘤生长明显抑制和抗肿瘤免疫增强。该降解剂还表现出良好的安全性，具有最小的靶外肿瘤毒性。此外，CD24-H7联合抗pd -1抗体协同促进肿瘤内CD8+ T细胞浸润和细胞毒性，同时减轻T细胞衰竭，与单一治疗相比，抗肿瘤疗效显著增强。这些发现强调了tfrc招募降解物选择性靶向膜蛋白的治疗潜力，并提供了一种令人信服的组合方法来克服肿瘤中的免疫逃避。

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引用次数: 0

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