Biochemical pharmacology最新文献_第10页

Targeting MRP4 in drug resistance and aspirin treatment failure: implications for precision medicine 靶向MRP4在耐药和阿司匹林治疗失败：对精准医学的影响。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-04-01 Epub Date: 2026-01-23 DOI: 10.1016/j.bcp.2026.117741

Simone De Corci, Eleonora Schiera, Sergio Terracina, Fabio M. Pulcinelli

Aspirin is widely used as an antiplatelet therapy for preventing and managing thrombotic complications in individuals at high risk. Nevertheless, growing evidence indicates that some patients continue to face cardiovascular events, suggesting impaired drug responsiveness or reduced sensitivity to aspirin.

This review primarily aims to elucidate a new emerging molecular mechanism underlying this clinical outcome. Recent studies propose that aspirin induces PPARα-dependent overexpression of the Multidrug Resistance Protein 4 (MRP4) transporter, leading to increased extrusion of aspirin and reduced drug efficacy. Several findings support this mechanism: i) MRP4 is associated with resistance to several drugs; ii) it is highly expressed in platelets, which are notably affected by aspirin; iii) it transports organic anions such as aspirin, which has been demonstrated to be a substrate; and iv) aspirin enhances PPARα activity, leading to higher MRP4 gene transcription.

Consequently, inhibition of MRP4-mediated aspirin efflux may enhance pharmacological efficacy and prevent platelet aggregation.

This review also highlights the potential role of lifelong monitoring in patients on aspirin therapy using platelet function tests to identify those with high residual platelet reactivity (RPR) despite treatment. Such monitoring helps detect inadequate antiplatelet response, guiding clinicians in selecting the most appropriate and personalised therapy, thereby optimising treatment efficacy and reducing the risk of recurrent thrombosis.

In conclusion, combining an MRP4 inhibitor with aspirin may represent a promising therapeutic strategy to overcome resistance mechanisms and improve clinical outcomes in patients who exhibit RPR on aspirin and MRP4 overexpression.

阿司匹林被广泛用作抗血小板治疗，用于预防和管理高危人群的血栓性并发症。然而，越来越多的证据表明，一些患者继续面临心血管事件，这表明药物反应性受损或对阿司匹林的敏感性降低。这篇综述的主要目的是阐明一个新的分子机制下的临床结果。最近的研究表明，阿司匹林诱导ppar α依赖性多药耐药蛋白4 （MRP4）转运体过表达，导致阿司匹林挤压增加，药物疗效降低。一些研究结果支持这一机制：1)MRP4与几种药物的耐药性有关；Ii)在血小板中高度表达，血小板受阿司匹林影响显著；Iii)运输有机阴离子，如阿司匹林，已被证明是一种底物；iv)阿司匹林增强PPARα活性，导致MRP4基因转录增加。因此，抑制mrp4介导的阿司匹林外排可能增强药理功效并防止血小板聚集。本综述还强调了终身监测阿司匹林治疗患者的潜在作用，使用血小板功能试验来识别治疗后残余血小板反应性（RPR）高的患者。这种监测有助于发现抗血小板反应不足，指导临床医生选择最合适和个性化的治疗方案，从而优化治疗效果，降低血栓复发的风险。总之，MRP4抑制剂联合阿司匹林可能是一种有希望的治疗策略，可以克服耐药机制，改善阿司匹林和MRP4过表达的RPR患者的临床结果。

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引用次数: 0

MKOP002, a novel bifunctional μ-/κ-opioid decapeptide with G protein-biased μ-opioid agonism, exhibits antinociceptive and antipruritic activities MKOP002是一种具有G蛋白偏向性μ-阿片激动作用的新型双功能μ-/κ-阿片十肽，具有抗疼痛和抗瘙痒活性。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-04-01 Epub Date: 2026-01-24 DOI: 10.1016/j.bcp.2026.117755

Shuyuan Wu , Kangtai Xu , Dan Chen, Jiamin Feng, Biao Xu, Ning Li, Nan Zhang, Mengna Zhang, Quan Fang

Opioid receptors, as members of the G-protein-coupled receptor (GPCR) superfamily, represent promising therapeutic targets for managing nociception. Herein, we designed, synthesized, and pharmacologically characterized the novel bifunctional decapeptide, MKOP002. In vitro, MKOP002 activated both µ- and κ-opioid receptors (MOR and KOR), exhibiting G protein-biased agonism at MOR. Subcutaneous (s.c.) injection of MKOP002 produced significant antinociceptive effects through the peripheral MOR and KOR in the tail-flick test. Notably, MKOP002 demonstrated potent and dose-dependent antinociceptive efficacy across various models of acute, inflammatory, and neuropathic pain. Additionally, MKOP002 exhibited antipruritic effects comparable to CR845, mediated by both the peripheral and central KOR. Similar to CR845, at the high doses, MKOP002 induced sedation via central KOR at least partially, and also resulted in depressive-like behaviors. Importantly, MKOP002 did not elicit MOR-associated adverse effects such as tolerance, constipation, respiratory depression, or addiction. These findings underscore the therapeutic potential of MKOP002 as a lead compound for antinociceptive and antipruritic therapy, supporting the development of bifunctional MOR/KOR agonists as a safer opioid strategy.

阿片受体，作为g蛋白偶联受体（GPCR）超家族的成员，代表了治疗痛觉的有希望的治疗靶点。在此，我们设计、合成了新型双功能十肽MKOP002，并对其进行了药理学表征。在体外，MKOP002激活μ -和κ-阿片受体（MOR和KOR），在MOR上表现出G蛋白偏向性激动作用。在甩尾试验中，通过外周MOR和KOR，皮下注射MKOP002产生了显著的抗伤感受作用。值得注意的是，MKOP002在各种急性、炎症和神经性疼痛模型中显示出有效的剂量依赖性抗伤害性疗效。此外，MKOP002表现出与CR845相当的抗瘙痒作用，由外周和中枢KOR介导。与CR845相似，在高剂量下，MKOP002至少部分通过中枢KOR诱导镇静，并导致抑郁样行为。重要的是，MKOP002没有引起mor相关的不良反应，如耐受性、便秘、呼吸抑制或成瘾。这些发现强调了MKOP002作为抗痛觉性和止痒性治疗先导化合物的治疗潜力，支持双功能MOR/KOR激动剂作为更安全的阿片类药物策略的发展。

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引用次数: 0

The myocardial ischemic cascade network and multi-target synergistic interventions: From molecular mechanisms to therapeutic innovations 心肌缺血级联网络和多靶点协同干预：从分子机制到治疗创新

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-04-01 Epub Date: 2026-01-14 DOI: 10.1016/j.bcp.2026.117704

Lei Qi , Jia Yi , Yuntian Shen , Haiyan Jiang , Xinlei Yao , Bingqian Chen , Hualin Sun

Myocardial ischemic injury involves a multi-layered pathological cascade driven by interconnected energy metabolism disorders, calcium overload, oxidative stress, mitochondrial dysfunction, and inflammatory responses. Ischemia-hypoxia impairs mitochondrial oxidative phosphorylation, causing ATP depletion, acidosis, and calcium overload. Reperfusion exacerbates injury through ROS burst, mPTP opening, and NLRP3 inflammasome activation, leading to pro-inflammatory cytokine release. Sustained endoplasmic reticulum stress promotes apoptosis via the PERK/CHOP pathway, forming a vicious cycle with oxidative stress and inflammation. These processes collectively trigger diverse programmed cell death modalities—apoptosis, pyroptosis, ferroptosis, necroptosis, and cuproptosis—while microcirculatory disturbances cause the “no-reflow” phenomenon, culminating in irreversible damage. Therapeutic strategies are shifting from revascularization to multi-target interventions. Reperfusion injury is mitigated by ischemic conditioning (IPoC, RIC) via RISK/SAFE pathways and ALDH2-SIRT3 axis activation. Cell death is targeted using ferroptosis inhibitors (e.g., Liproxstatin-1), NLRP3/caspase-1 blockers, and autophagy regulators (e.g., Astragaloside IV). Mitochondrial/metabolic therapies include mitochondrial-targeted drugs (e.g., CsA@PLGA-PEG-SS31), metabolic modulators (Trimetazidine), and neuroendocrine agents (ARNI, SGLT2 inhibitors). Regenerative approaches employ stem cells/exosomes, gene therapy, and tissue engineering via paracrine signaling. Precision medicine integrates multi-omics and AI for risk stratification, while biomimetic nanocarriers enhance drug delivery. Future therapies should co-target the “energy-death-inflammation” network to advance myocardial ischemia treatment toward systemic repair and improved clinical outcomes.

心肌缺血损伤涉及一个多层次的病理级联反应，由相互关联的能量代谢紊乱、钙超载、氧化应激、线粒体功能障碍和炎症反应驱动。缺血-缺氧损害线粒体氧化磷酸化，引起ATP耗竭、酸中毒和钙超载。再灌注通过ROS爆发、mPTP开放和NLRP3炎性体激活加剧损伤，导致促炎细胞因子释放。持续的内质网应激通过PERK/CHOP途径促进细胞凋亡，与氧化应激和炎症形成恶性循环。这些过程共同引发不同的程序性细胞死亡模式——凋亡、焦亡、铁亡、坏死亡和铜亡——而微循环紊乱导致“无回流”现象，最终导致不可逆的损伤。治疗策略正从血运重建术转向多靶点干预。缺血调节（IPoC， RIC）通过RISK/SAFE通路和ALDH2-SIRT3轴激活减轻再灌注损伤。细胞死亡的目标是使用铁凋亡抑制剂（如利普司他汀-1）、NLRP3/caspase-1阻滞剂和自噬调节剂（如黄芪甲苷IV）。线粒体/代谢治疗包括线粒体靶向药物（例如CsA@PLGA-PEG-SS31）、代谢调节剂（曲美他嗪）和神经内分泌药物（ARNI、SGLT2抑制剂）。再生方法采用干细胞/外泌体、基因治疗和通过旁分泌信号传导的组织工程。精准医学结合多组学和人工智能进行风险分层，仿生纳米载体增强药物传递。未来的治疗应共同靶向“能量-死亡-炎症”网络，以推进心肌缺血治疗走向全身修复和改善临床结果。

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引用次数: 0

LIFR antagonism reverses epithelial pro-CAF programs in pancreatic ductal adenocarcinoma LIFR拮抗剂逆转胰腺导管腺癌上皮前caf程序。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-04-01 Epub Date: 2026-01-14 DOI: 10.1016/j.bcp.2026.117707

Cristina Di Giorgio , Maria Rosaria Sette , Benedetta Sensini , Eleonora Giannelli , Ginevra Lachi , Silvia Marchianò , Francesca Paniconi , Carmen Massa , Ginevra Urbani , Rosa De Gregorio , Valentina Sepe , Maria Chiara Monti , Federica Moraca , Bruno Catalanotti , Fabio Cartaginese , Eleonora Distrutti , Angela Zampella , Michele Biagioli , Stefano Fiorucci

Extracellular matrix remodelling that occurs in pancreatic ductal adenocarcinoma (PDAC) is considered a promoting factor of cancer growth, immune evasion and therapeutic resistance. Cancer-associated fibroblasts (CAFs) that constitute the dominant stromal population, arise primarily from activated pancreatic stellate cells and display remarkable functional heterogeneity, encompassing inflammatory iCAFs and contractile myCAFs. Although epithelial-stromal communication is central to PDAC biology, the upstream mechanisms that prime tumour cells toward CAF-Activating cells remain incompletely defined. The leukaemia inhibitory factor (LIF), a pleiotropic cytokine of the IL-6 family, is highly expressed in PDAC and has been implicated in tumour progression. However, the role of LIF and LIF receptor (LIFR):gp130 complex in promoting CAF activation is poorly defined. Here, we combined human PDAC transcriptomics, immunofluorescence and epithelial-stromal co-culture assays to define LIF-driven pro-CAF programs and evaluate their pharmacological reversibility. In PDAC cancer cells, MIAPaCa-2 cells, LIF induced a coordinated transcriptional network encompassing inflammatory mediators, paracrine fibroblast-activating signals and ECM/mechanotransductive modules, while repressing stromal-inhibitory genes. These signatures were recapitulated in PDAC tissues, where LIF expression directly correlated with CAF markers and with stromal remodelling genes. On this background, we have developed a novel steroidal LIFR antagonist, LRI310, and evaluate its effects on LIF:LIFR axis. Exposure of PDCA cell lines to LRI310 suppresses STAT3 activation and counteracts effects of LIF on proliferation and CAF-inducing transcriptional programs. Collectively, these findings identify LIF as an important epithelial driver of CAF-oriented transcriptional programs in PDAC and support the development of LIFR antagonism as a promising strategy to modulate the desmoplastic microenvironment.

发生在胰腺导管腺癌（PDAC）的细胞外基质重构被认为是促进肿瘤生长、免疫逃避和治疗抵抗的因素。癌相关成纤维细胞（CAFs）构成了主要的基质群体，主要来自活化的胰腺星状细胞，并显示出显著的功能异质性，包括炎症性icaf和收缩性myCAFs。尽管上皮间质通讯是PDAC生物学的核心，但将肿瘤细胞引向cafa激活细胞的上游机制仍未完全确定。白血病抑制因子（LIF）是IL-6家族的一种多效性细胞因子，在PDAC中高度表达，并与肿瘤进展有关。然而，LIF和LIF受体（LIFR）：gp130复合物在促进CAF激活中的作用尚不明确。在这里，我们结合了人类PDAC转录组学，免疫荧光和上皮-基质共培养分析来定义lifd驱动的前caf程序并评估其药理学可逆性。在PDAC癌细胞、MIAPaCa-2细胞中，LIF诱导了一个协调的转录网络，包括炎症介质、旁分泌成纤维细胞激活信号和ECM/机械转导模块，同时抑制基质抑制基因。这些特征在PDAC组织中重现，其中LIF表达与CAF标记物和基质重塑基因直接相关。在此背景下，我们开发了一种新的甾体LIFR拮抗剂LRI310，并评估了其对LIFR轴的作用。暴露于LRI310的PDCA细胞系可抑制STAT3的激活，并抵消LIF对增殖和ca诱导转录程序的影响。总的来说，这些发现确定了LIFR是PDAC中ca导向转录程序的重要上皮驱动因素，并支持LIFR拮抗剂作为调节结缔组织微环境的有前途的策略的发展。

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引用次数: 0

Valine availability controls oncogenic cell-cycle progression through translation of D-type cyclins 缬氨酸的有效性通过翻译d型细胞周期蛋白来控制致癌细胞周期的进程。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-04-01 Epub Date: 2026-01-13 DOI: 10.1016/j.bcp.2026.117706

Tomoaki Yamauchi , Runa Fukuzaki , Yumi Takahata , Yumi Okano , Kouki Suzuki , Akito Tsuruta , Shigehiro Ohdo , Satoru Koyanagi

Although rapid proliferation of cancer cells imposes a heightened demand for specific amino acids, the mechanistic links between amino acid availability and cell cycle regulation remain poorly defined. Valine, a branched-chain amino acid, is traditionally recognized for its role in protein synthesis and energy metabolism, but its direct influence on malignant cell growth has not been established. Here, we identify intracellular valine as a critical regulator of oncogenic cell cycle progression. Across murine hepatocarcinoma, breast cancer, renal cancer, colorectal adenocarcinoma, valine deprivation triggered G₀/G₁ phase arrest and potently suppressed their proliferation. Mechanistically, valine depletion upregulated eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which repressed cyclin D1 and D2 translation by sequestering eukaryotic translation initiation factor 4E (eIF4E). Concurrently, valine deprivation induced Sestrin2 expression and inhibited mammalian target of rapamycin (mTOR) activity, converging to attenuate mRNA translation. These findings uncover a previously unrecognized role of valine as a direct molecular controller of the cancer cell cycle, acting through translational repression of D-type cyclins. Targeting exogenous valine supply, in combination with cell cycle–directed therapies, may offer a promising strategy to suppress the growth of malignant tumors.

尽管癌细胞的快速增殖增加了对特定氨基酸的需求，但氨基酸可用性和细胞周期调节之间的机制联系仍然不清楚。缬氨酸是一种支链氨基酸，传统上认为它在蛋白质合成和能量代谢中起作用，但它对恶性细胞生长的直接影响尚未确定。在这里，我们确定细胞内缬氨酸是致癌细胞周期进程的关键调节剂。在小鼠肝癌、乳腺癌、肾癌、结直肠腺癌中，缬氨酸剥夺可触发G0/G1期阻滞并有效抑制其增殖。从机制上讲，缬氨酸缺失上调真核翻译起始因子4E结合蛋白1 (4E- bp1)，该蛋白通过隔离真核翻译起始因子4E （eIF4E）抑制cyclin D1和D2的翻译。同时，缬氨酸剥夺诱导了Sestrin2的表达，抑制了哺乳动物雷帕霉素靶蛋白（mTOR）的活性，从而减弱mRNA的翻译。这些发现揭示了先前未被认识到的缬氨酸作为癌细胞周期的直接分子控制器的作用，通过d型细胞周期蛋白的翻译抑制起作用。靶向外源性缬氨酸供应，结合细胞周期导向疗法，可能为抑制恶性肿瘤的生长提供一种有希望的策略。

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引用次数: 0

ATF4 in cardiovascular diseases: an emerging therapeutic target ATF4在心血管疾病中的作用：一个新兴的治疗靶点。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-04-01 Epub Date: 2026-01-10 DOI: 10.1016/j.bcp.2026.117703

Luning Qin , Ruolan Chen , Chao Huang , Xuezhe Wang , Qinghang Song , Zhaoqing Li , Xiaojian Xu , Zhijun Liu , Banghui Wang , Bing Li , Xian-Ming Chu

Activating transcription factor 4 (ATF4), as a core regulatory factor of the activating transcription factor (ATF)/cAMP-response element binding protein (CREB) family, governs cell fate determination through endoplasmic reticulum stress(ERS), autophagy, and redox networks. The dynamic balance of its functions is crucial for maintaining cardiovascular homeostasis; however, there remains a significant lack of systematic understanding of its regulatory mechanisms. To address the aforementioned research gap, this article systematically elucidates the dynamic regulatory network of ATF4 in cardiovascular diseases (CVDs), constructs its interaction relationship map, and highlights three critical scientific issues that urgently need to be resolved: the cell-type-specific epigenetic regulatory network of ATF4, precise intervention strategies for spatiotemporally specific ATF4 activation, and the development of tissue-targeted ATF4 modulators. Breakthroughs in these research directions are expected to provide novel therapeutic strategies for CVDs targeting the ATF4-mediated metabolic-death axis.

激活转录因子4 （ATF4）是激活转录因子(ATF)/ camp反应元件结合蛋白（CREB）家族的核心调控因子，通过内质网应激（ERS）、自噬和氧化还原网络决定细胞命运。其功能的动态平衡对维持心血管稳态至关重要；然而，对其调控机制仍然缺乏系统的认识。为了弥补上述研究空白，本文系统阐述了ATF4在心血管疾病（cvd）中的动态调控网络，构建了其相互作用关系图，并突出了ATF4细胞特异性表观遗传调控网络、ATF4时空特异性激活的精准干预策略、组织靶向ATF4调节剂的开发等三个亟待解决的关键科学问题。这些研究方向的突破有望为针对atf4介导的代谢-死亡轴的心血管疾病提供新的治疗策略。

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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 : 2026-04-01 Epub 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

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 : 2026-04-01 Epub 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

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 : 2026-04-01 Epub 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 : 2026-04-01 Epub 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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