Pharmacological research最新文献_第9页

From fuel to epigenetic signal: Lactate-lactylation axis orchestrates diabetic complications 从燃料到表观遗传信号：乳酸-乳酸化轴协调糖尿病并发症。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108052

Siyu Guo , Min Ye , Wengen Zhu , Chen Liu

Lactate, traditionally regarded as a metabolic waste product, is now recognized as a pivotal signaling molecule and epigenetic regulator. Emerging evidence indicates that the metabolic reprogramming driven by hyperglycemia elevates the overall levels of lactate and lactylation, further promoting the progression of diabetes mellitus. This review emphasizes that lactate-lactylation axis dysregulation serves as a unified mechanism to drive multiple diabetic complications-diabetic cardiomyopathy, diabetic kidney disease, diabetic retinopathy, and median vascular calcification. Abnormal lactate metabolism enhances global lactylation levels, which remodels macrophage polarization, disrupts mitochondrial function, aggravates fibrosis and aberrant angiogenesis. Mechanistically, lactylation is dynamically modulated by writers (e.g., p300/CBP), erasers (e.g., HDAC1–3), regulators (e.g., GPR81), and profoundly impacts gene expression and protein functions in both histone and non-histone modifications. Nonetheless, key questions remain unresolved, such as the contextual duality of lactylation in either resolving or aggravating inflammation, and the uncertainties of enzymatic route for mammalian lactyl-CoA formation, suggesting that lactylation-associated evidence is still limited. Ultimately, this review underscores the therapeutic potential for diabetic complications management by targeting lactate-lactylation axis in metabolic-epigenetic manner.

乳酸，传统上被认为是一种代谢废物，现在被认为是一个关键的信号分子和表观遗传调节剂。新出现的证据表明，高血糖导致的代谢重编程提高了乳酸和乳酸化的总体水平，进一步促进了糖尿病的进展。本综述强调乳酸-乳酸化轴失调是驱动糖尿病多种并发症（糖尿病心肌病、糖尿病肾病、糖尿病视网膜病变和正中血管钙化）的统一机制。乳酸代谢异常会提高整体乳酸化水平，从而重塑巨噬细胞极化，破坏线粒体功能，加重纤维化和血管生成异常。从机制上讲，乳酸化是由写入器（如p300/CBP）、擦除器（如HDAC1-3）、调节器（如GPR81）动态调节的，并在组蛋白和非组蛋白修饰中深刻影响基因表达和蛋白质功能。尽管如此，关键问题仍未解决，如乳酸化在缓解或加重炎症中的背景二元性，以及哺乳动物乳酸辅酶a形成的酶促途径的不确定性，表明与乳酸化相关的证据仍然有限。最后，本综述强调了以代谢-表观遗传方式靶向乳酸-乳酸化轴治疗糖尿病并发症的治疗潜力。

{"title":"From fuel to epigenetic signal: Lactate-lactylation axis orchestrates diabetic complications","authors":"Siyu Guo , Min Ye , Wengen Zhu , Chen Liu","doi":"10.1016/j.phrs.2025.108052","DOIUrl":"10.1016/j.phrs.2025.108052","url":null,"abstract":"<div><div>Lactate, traditionally regarded as a metabolic waste product, is now recognized as a pivotal signaling molecule and epigenetic regulator. Emerging evidence indicates that the metabolic reprogramming driven by hyperglycemia elevates the overall levels of lactate and lactylation, further promoting the progression of diabetes mellitus. This review emphasizes that lactate-lactylation axis dysregulation serves as a unified mechanism to drive multiple diabetic complications-diabetic cardiomyopathy, diabetic kidney disease, diabetic retinopathy, and median vascular calcification. Abnormal lactate metabolism enhances global lactylation levels, which remodels macrophage polarization, disrupts mitochondrial function, aggravates fibrosis and aberrant angiogenesis. Mechanistically, lactylation is dynamically modulated by writers (e.g., p300/CBP), erasers (e.g., HDAC1–3), regulators (e.g., GPR81), and profoundly impacts gene expression and protein functions in both histone and non-histone modifications. Nonetheless, key questions remain unresolved, such as the contextual duality of lactylation in either resolving or aggravating inflammation, and the uncertainties of enzymatic route for mammalian lactyl-CoA formation, suggesting that lactylation-associated evidence is still limited. Ultimately, this review underscores the therapeutic potential for diabetic complications management by targeting lactate-lactylation axis in metabolic-epigenetic manner.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108052"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Integrating a genotype-based follow-up algorithm in clinical surveillance to mitigate the risk of pancreatitis in patients treated with GLP-1R agonists 在临床监测中整合基于基因型的随访算法，以降低GLP-1R激动剂治疗的患者发生胰腺炎的风险。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108060

Angeliki Margoni, Athanasios G. Papavassiliou

引用次数: 0

A clinically relevant pan-cancer prognostic signature derived from T-cell activation immune genes: Experimental validation across malignancies with emphasis on breast cancer 来自t细胞活化免疫基因的临床相关泛癌预后特征：在恶性肿瘤中的实验验证，重点是乳腺癌。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108044

Jia-Ning Zhang , Xi-Rui Zhou , Yu-tong Wang , Zi-lu Yi , Lin-wei Li , Hong Liu

T-cell activation is widely recognized as a pivotal anti-tumor mechanism, yet emerging evidence reveals functional heterogeneity among T-cell subtypes within the tumor microenvironment (TME). To address this complexity, we developed a pan-cancer prognostic model to systematically evaluate the roles of T-cell activation-related immune response genes (TCR-IRGs) across malignancies. Pan-cancer transcriptomic data from UCSC Xena were analyzed. Through LASSO Cox regression, a prognostic signature comprising 23 TCR-IRGs was established.The high-risk score was significantly associated with aggressive malignant phenotypes, including enhanced epithelial mesenchymal transition and tumor proliferation. Further investigation focused on PTGER4, a gene within the signature predominantly expressed in T cells, as revealed by single-cell RNA sequencing analysis in breast tissues. Mechanistically, PTGER4 expression correlated with multiple immune checkpoints. In mouse models, PTGER4 overexpression enhanced the efficacy of PD-1 blockade by promoting CD8⁺ T cell infiltration and function, as indicated by increased levels of IFN-γ and Granzyme B. This study establishes a TME-centric prognostic framework, revealing that while the composite TCR-IRGs score generally indicates a higher risk of tumor progression, individual components like PTGER4 may paradoxically mark a T-cell state amenable to reinvigoration by immunotherapy, highlighting the context-dependent utility of immune biomarkers in oncology.

t细胞活化被广泛认为是一种关键的抗肿瘤机制，但新的证据显示肿瘤微环境（TME）中t细胞亚型之间的功能异质性。为了解决这一复杂性，我们开发了一个泛癌症预后模型来系统评估t细胞激活相关免疫反应基因（TCR-IRGs）在恶性肿瘤中的作用。分析来自UCSC Xena的泛癌转录组数据。通过LASSO - Cox回归，建立了包括23个TCR-IRGs的预后特征。高风险评分与侵袭性恶性表型显著相关，包括上皮间质转移增强和肿瘤增殖。进一步的研究集中在PTGER4上，这是一个主要在T细胞中表达的特征基因，在乳腺癌的单细胞RNA测序分析中发现。机制上，PTGER4表达与多个免疫检查点相关。在小鼠模型中，PTGER4过表达通过促进CD8 + T细胞浸润和功能来增强PD-1阻断的疗效，正如IFN-γ和颗粒酶b水平的增加所表明的那样。这项研究建立了一个以tme为中心的预后框架，揭示了虽然TCR-IRG复合评分通常表明肿瘤进展的风险更高，但PTGER4等单个成分可能悖论地标志着一种可通过免疫治疗重新激活的T细胞状态。强调免疫生物标志物在肿瘤学中的情境依赖性效用。

{"title":"A clinically relevant pan-cancer prognostic signature derived from T-cell activation immune genes: Experimental validation across malignancies with emphasis on breast cancer","authors":"Jia-Ning Zhang , Xi-Rui Zhou , Yu-tong Wang , Zi-lu Yi , Lin-wei Li , Hong Liu","doi":"10.1016/j.phrs.2025.108044","DOIUrl":"10.1016/j.phrs.2025.108044","url":null,"abstract":"<div><div>T-cell activation is widely recognized as a pivotal anti-tumor mechanism, yet emerging evidence reveals functional heterogeneity among T-cell subtypes within the tumor microenvironment (TME). To address this complexity, we developed a pan-cancer prognostic model to systematically evaluate the roles of T-cell activation-related immune response genes (TCR-IRGs) across malignancies. Pan-cancer transcriptomic data from UCSC Xena were analyzed. Through LASSO Cox regression, a prognostic signature comprising 23 TCR-IRGs was established.The high-risk score was significantly associated with aggressive malignant phenotypes, including enhanced epithelial mesenchymal transition and tumor proliferation. Further investigation focused on PTGER4, a gene within the signature predominantly expressed in T cells, as revealed by single-cell RNA sequencing analysis in breast tissues. Mechanistically, PTGER4 expression correlated with multiple immune checkpoints. In mouse models, PTGER4 overexpression enhanced the efficacy of PD-1 blockade by promoting CD8⁺ T cell infiltration and function, as indicated by increased levels of IFN-γ and Granzyme B. This study establishes a TME-centric prognostic framework, revealing that while the composite TCR-IRGs score generally indicates a higher risk of tumor progression, individual components like PTGER4 may paradoxically mark a T-cell state amenable to reinvigoration by immunotherapy, highlighting the context-dependent utility of immune biomarkers in oncology.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108044"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Spatial proteomic profiling reveals conserved prognostic immune microenvironment features across molecular subtypes in small cell lung cancer 空间蛋白质组学分析揭示了小细胞肺癌分子亚型中保守的预后免疫微环境特征。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108048

Modi Zhai , Zicheng Zhang , Jiyan Dong , Zhuo Li , Yuqing Cao , Ruanqi Chen , Meng Zhou , Lin Yang

Small cell lung cancer (SCLC) molecular subtypes, defined by neuroendocrine (NE) status and transcription factor (TF) expression, provide insight into tumor biology but fails to fully capture the spatial complexity of the immune microenvironment (IME) and possess limited prognostic power. In this study, we performed an integrative analysis of targeted bulk transcriptomics, spatial proteomics and immunohistochemistry (IHC) with extensive multiregional sampling across central tumor (CT), invasive margin (IM), and peri-tumoral (PT) compartments in treatment-naïve formalin-fixed, paraffin-embedded SCLC samples to investigate the IME heterogeneity and its clinical significance across molecular subtypes. Targeted bulk transcriptomics of immune gene panel identified two major immune groups, immune-hot group (IHG) and immune-cold group (ICG), which are associated with NE status but independent of TF subtypes and showed limited prognostic value. In contrast, spatial proteomic profiling revealed profound spatial immune heterogeneity within individual tumors, and identified immune activation specifically within the CT as a dominant and independent prognostic biomarker that transcends traditional NE and TF subtypes. IHG-CT tumors, characterized by enriched cytotoxic T cells, activated antigen presentation, and myeloid engagement, were significantly associated with improved survival outcomes, whereas immune heterogeneity in the IM and PT regions did not correlate with survival outcomes, as validated by IHC. Additionally, the IHG status was associated with clinical benefit from immune checkpoint blockade. Collectively, our study highlights the importance of spatial context for understanding clinically relevant IME features, and provides a transformative spatially informed framework for SCLC patient stratification and therapeutic development.

由神经内分泌（NE）状态和转录因子（TF）表达定义的小细胞肺癌（SCLC）分子亚型提供了对肿瘤生物学的深入了解，但未能完全捕获免疫微环境（IME）的空间复杂性，并且具有有限的预后能力。在这项研究中，我们对treatment-naïve福尔马林固定、石蜡包埋的SCLC样本进行了靶向大量转录组学、数字空间蛋白质组学（DSP）和多重免疫组织化学（IHC）的综合分析，并在肿瘤核心（CT）、浸润边缘（IM）和肿瘤周围（PT）区室进行了广泛的多区域采样，以研究IME在不同分子亚型之间的异质性及其临床意义。免疫基因小组的靶向大量转录组学鉴定出两个主要的免疫亚群，免疫热（IHG）和免疫冷（ICG），它们与NE状态相关，但独立于TF亚型，显示出有限的预后价值。相比之下，DSP分析揭示了个体肿瘤内深刻的空间免疫异质性，并明确了肿瘤核心内的免疫激活是超越传统NE和TF亚型的主要和独立的预后生物标志物。IHG-CT肿瘤的特点是细胞毒性T细胞富集、抗原呈递活化和骨髓接合，与改善的生存结果显著相关，而IM和PT区域的免疫异质性与生存结果无关，多重IHC证实了这一点。此外，IHG状态与免疫检查点阻断的临床获益相关。总的来说，我们的研究强调了空间背景对理解临床相关IME特征的重要性，并为SCLC患者分层和治疗发展提供了一个变革性的空间信息框架。

{"title":"Spatial proteomic profiling reveals conserved prognostic immune microenvironment features across molecular subtypes in small cell lung cancer","authors":"Modi Zhai , Zicheng Zhang , Jiyan Dong , Zhuo Li , Yuqing Cao , Ruanqi Chen , Meng Zhou , Lin Yang","doi":"10.1016/j.phrs.2025.108048","DOIUrl":"10.1016/j.phrs.2025.108048","url":null,"abstract":"<div><div>Small cell lung cancer (SCLC) molecular subtypes, defined by neuroendocrine (NE) status and transcription factor (TF) expression, provide insight into tumor biology but fails to fully capture the spatial complexity of the immune microenvironment (IME) and possess limited prognostic power. In this study, we performed an integrative analysis of targeted bulk transcriptomics, spatial proteomics and immunohistochemistry (IHC) with extensive multiregional sampling across central tumor (CT), invasive margin (IM), and peri-tumoral (PT) compartments in treatment-naïve formalin-fixed, paraffin-embedded SCLC samples to investigate the IME heterogeneity and its clinical significance across molecular subtypes. Targeted bulk transcriptomics of immune gene panel identified two major immune groups, immune-hot group (IHG) and immune-cold group (ICG), which are associated with NE status but independent of TF subtypes and showed limited prognostic value. In contrast, spatial proteomic profiling revealed profound spatial immune heterogeneity within individual tumors, and identified immune activation specifically within the CT as a dominant and independent prognostic biomarker that transcends traditional NE and TF subtypes. IHG-CT tumors, characterized by enriched cytotoxic T cells, activated antigen presentation, and myeloid engagement, were significantly associated with improved survival outcomes, whereas immune heterogeneity in the IM and PT regions did not correlate with survival outcomes, as validated by IHC. Additionally, the IHG status was associated with clinical benefit from immune checkpoint blockade. Collectively, our study highlights the importance of spatial context for understanding clinically relevant IME features, and provides a transformative spatially informed framework for SCLC patient stratification and therapeutic development.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108048"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The ARK side of the cell: Kinases, metabolism, and therapeutic potential in malignancies 细胞的ARK侧：激酶、代谢和恶性肿瘤的治疗潜力。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108056

Viviana Coliboro-Dannich , Alejandro Farías , Luis Espinoza-Francine , M. Andrea Concha-Vega , Karen Almendras-Durán , Ana María Salazar , Roxana Pincheira , Ariel Fernando Castro

The human AMP-activated protein kinase (AMPK)-related kinases (ARKs) are a conserved family of serine/threonine kinases primarily activated by liver kinase B1 (LKB1). ARKs play crucial roles in various cellular processes, particularly in energy metabolism and stress signaling pathways. While AMPK is well-known as a key regulator of energy homeostasis, its paralogs have emerged as significant modulators of metabolic adaptation, signal transduction, and tumorigenesis, placing them at the center of cancer cell physiology. This review provides a comprehensive overview of the ARKs family, detailing their structural features, regulatory mechanisms, and activation pathways. We categorized ARKs by shared molecular mechanisms and tumorigenic roles, highlighting their complex involvement in cancer. Understanding the functions of ARKs in cancer and other diseases unveils an important and often overlooked layer of metabolic and stress regulation. As research continues to clarify their roles, ARKs are becoming recognized as promising yet largely underexplored contributors to tumor biology. This knowledge provides valuable insights into cellular adaptation and presents new opportunities for targeted therapeutic strategies in cancer treatment.

人amp活化蛋白激酶（AMPK）相关激酶（ARKs）是一个保守的丝氨酸/苏氨酸激酶家族，主要由肝激酶B1 （LKB1）激活。ARKs在多种细胞过程中起着至关重要的作用，特别是在能量代谢和应激信号通路中。众所周知，AMPK是能量稳态的关键调节因子，其类似物已成为代谢适应、信号转导和肿瘤发生的重要调节因子，使其处于癌细胞生理学的中心。本文综述了ARKs家族，详细介绍了它们的结构特征、调控机制和激活途径。我们根据共享的分子机制和致瘤作用对ARKs进行分类，强调了它们在癌症中的复杂参与。了解ARKs在癌症和其他疾病中的功能揭示了代谢和应激调节的一个重要且经常被忽视的层面。随着研究继续阐明它们的作用，ARKs被认为是肿瘤生物学中有希望但尚未充分开发的贡献者。这些知识为细胞适应提供了有价值的见解，并为癌症治疗的靶向治疗策略提供了新的机会。

{"title":"The ARK side of the cell: Kinases, metabolism, and therapeutic potential in malignancies","authors":"Viviana Coliboro-Dannich , Alejandro Farías , Luis Espinoza-Francine , M. Andrea Concha-Vega , Karen Almendras-Durán , Ana María Salazar , Roxana Pincheira , Ariel Fernando Castro","doi":"10.1016/j.phrs.2025.108056","DOIUrl":"10.1016/j.phrs.2025.108056","url":null,"abstract":"<div><div>The human AMP-activated protein kinase (AMPK)-related kinases (ARKs) are a conserved family of serine/threonine kinases primarily activated by liver kinase B1 (LKB1). ARKs play crucial roles in various cellular processes, particularly in energy metabolism and stress signaling pathways. While AMPK is well-known as a key regulator of energy homeostasis, its paralogs have emerged as significant modulators of metabolic adaptation, signal transduction, and tumorigenesis, placing them at the center of cancer cell physiology. This review provides a comprehensive overview of the ARKs family, detailing their structural features, regulatory mechanisms, and activation pathways. We categorized ARKs by shared molecular mechanisms and tumorigenic roles, highlighting their complex involvement in cancer. Understanding the functions of ARKs in cancer and other diseases unveils an important and often overlooked layer of metabolic and stress regulation. As research continues to clarify their roles, ARKs are becoming recognized as promising yet largely underexplored contributors to tumor biology. This knowledge provides valuable insights into cellular adaptation and presents new opportunities for targeted therapeutic strategies in cancer treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108056"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Cell transplantation therapies in Huntington’s disease – Current status and future directions 细胞移植治疗亨廷顿氏病-现状和未来的方向。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108025

Angelica E. Guiloff, Roger A. Barker

引用次数: 0

Overcoming ELDR-mediated cancer cell survival in vitro and in vivo via sphingomyelin-driven TRPML1 inactivation and TFEB suppression through lysosomal HSP70 targeting 通过鞘磷脂驱动的TRPML1失活和通过溶酶体HSP70靶向抑制TFEB，克服eldr介导的癌细胞体外和体内存活

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108050

Hongyu Chen , Mengyuan Zhu , Ziying Zhao , Yuexin Jiang , Haidi Wang , Yu Liu , Yan Chen , Hui Li , Chen Xun , Hui Hui

Lysosomal adaptation through the endo-lysosomal damage response (ELDR) enables cancer cells to evade lysosome-targeted therapies. Here, we identified the flavonoid compound V8 as a first-in-class ELDR disruptor that eliminated cancer cells by sabotaging lysosomal resilience. Mechanistically, V8 bound lysosomal HSP70 via hydrogen bonding, destabilizing its interaction with bis(monoacylglycero)phosphate (BMP) and triggering pathological sphingomyelin (SM) accumulation. SM overload allosterically inhibited TRPML1, blocking calcineurin PPP3CB activation and subsequent TFEB dephosphorylation. This dual perturbation: enhanced lysophagy and failed TFEB-driven biogenesis drove catastrophic lysosomal bankruptcy. Crucially, V8 bypassed canonical ELDR activation: unlike lysosomotropic agent LLOMe, it induced global membrane remodeling rather than focal perforations, avoiding Ca²⁺-dependent endosomal sorting complexes required for transport (ESCRT) repair. Genetic validation using HSP70-knockout and point mutation models confirmed target specificity, while SM synthase inhibition rescued TRPML1 activity and mitigated apoptosis. Tumor-selective efficacy arose from malignant cells’ heightened SM dependency and lysosomal HSP70 reliance, sparing normal counterparts. Our work established HSP70-BMP-ASM axis disruption as a strategy to subvert lysosomal homeostasis, providing a blueprint for next-generation lysosome-targeting agents that exploit lipid-mediated channelopathy to sensitize cancer cells to lysosomal damage.

通过内溶酶体损伤反应（ELDR）的溶酶体适应使癌细胞逃避溶酶体靶向治疗。在这里，我们确定了类黄酮化合物V8作为一流的ELDR干扰物，通过破坏溶酶体的弹性来消除癌细胞。在机制上，V8通过氢键结合溶酶体HSP70，破坏其与BMP（单酰基甘油）磷酸（BMP）的相互作用，引发病理性鞘磷脂（SM）积累。SM超载变构性地抑制TRPML1，阻断钙调磷酸酶PPP3CB的激活和随后的TFEB去磷酸化。这种双重扰动：溶体吞噬增强和tfeb驱动的生物发生失败，导致了灾难性的溶酶体破产。关键是，V8绕过了典型的ELDR激活：与溶酶体增溶剂LLOMe不同，它诱导了全局膜重构，而不是局部穿孔，避免了运输（ESCRT）修复所需的Ca 2 +依赖的内体分选复合物。使用hsp70敲除和点突变模型进行的遗传验证证实了靶特异性，而SM合成酶抑制可挽救TRPML1活性并减轻细胞凋亡。肿瘤选择性疗效源于恶性细胞对SM的高度依赖和对溶酶体HSP70的依赖，而正常细胞则不受影响。我们的工作建立了HSP70-BMP-ASM轴破坏作为一种破坏溶酶体稳态的策略，为下一代溶酶体靶向药物提供了蓝图，这些药物利用脂质介导的通道病变使癌细胞对溶酶体损伤敏感。

{"title":"Overcoming ELDR-mediated cancer cell survival in vitro and in vivo via sphingomyelin-driven TRPML1 inactivation and TFEB suppression through lysosomal HSP70 targeting","authors":"Hongyu Chen , Mengyuan Zhu , Ziying Zhao , Yuexin Jiang , Haidi Wang , Yu Liu , Yan Chen , Hui Li , Chen Xun , Hui Hui","doi":"10.1016/j.phrs.2025.108050","DOIUrl":"10.1016/j.phrs.2025.108050","url":null,"abstract":"<div><div>Lysosomal adaptation through the endo-lysosomal damage response (ELDR) enables cancer cells to evade lysosome-targeted therapies. Here, we identified the flavonoid compound V8 as a first-in-class ELDR disruptor that eliminated cancer cells by sabotaging lysosomal resilience. Mechanistically, V8 bound lysosomal HSP70 via hydrogen bonding, destabilizing its interaction with bis(monoacylglycero)phosphate (BMP) and triggering pathological sphingomyelin (SM) accumulation. SM overload allosterically inhibited TRPML1, blocking calcineurin PPP3CB activation and subsequent TFEB dephosphorylation. This dual perturbation: enhanced lysophagy and failed TFEB-driven biogenesis drove catastrophic lysosomal bankruptcy. Crucially, V8 bypassed canonical ELDR activation: unlike lysosomotropic agent LLOMe, it induced global membrane remodeling rather than focal perforations, avoiding Ca²⁺-dependent endosomal sorting complexes required for transport (ESCRT) repair. Genetic validation using HSP70-knockout and point mutation models confirmed target specificity, while SM synthase inhibition rescued TRPML1 activity and mitigated apoptosis. Tumor-selective efficacy arose from malignant cells’ heightened SM dependency and lysosomal HSP70 reliance, sparing normal counterparts. Our work established HSP70-BMP-ASM axis disruption as a strategy to subvert lysosomal homeostasis, providing a blueprint for next-generation lysosome-targeting agents that exploit lipid-mediated channelopathy to sensitize cancer cells to lysosomal damage.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108050"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Selective HDAC6 inhibition by Mesinostat impairs tumor growth and stemness in triple-negative breast cancer Mesinostat选择性抑制HDAC6影响三阴性乳腺癌的肿瘤生长和干性

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108055

Ivana Bello , Simona Barone , Anna Guadagni, Camilla Esposito, Morena D’Ariano, Martina Smimmo, Giuseppe Cirino, Vincenzo Summa, Margherita Brindisi , Elisabetta Panza

Triple-negative breast cancer (TNBC) remains the most aggressive breast cancer subtype, accounting for over half of breast cancer-related deaths. In the era of precision oncology, epigenetic dysregulation has emerged as a key driver of breast tumorigenesis. Among epigenetic targets, histone deacetylase 6 (HDAC6) has attracted increasing attention due to its cytoplasmic localization and regulation of non-histone substrates such as Hsp90, α-tubulin, and cortactin. We recently identified a novel class of spirocyclic molecules as potent and selective HDAC6 inhibitors. Here, we investigated the pharmacological profile of Mesinostat, one of the most selective compounds of this series, in human TNBC cell lines, 3D spheroids, and patient-derived organoids (PDOs) from lymph node metastases. In TNBC cells, using western blot analysis, we demonstrated that Mesinostat (1–30 µM) selectively inhibited HDAC6 by increasing acetylated α-tubulin levels, with no effect on the histone H3 acetylation. Yet, Mesinostat markedly reduced cell proliferation through apoptosis, cell cycle arrest, and autophagy. Furthermore, it inhibited epithelial-mesenchymal transition, decreased cell migration, and disrupted spheroid integrity. Treatment of PDOs led to a dose-dependent reduction in viability and clonogenic capacity, accompanied by downregulation of stemness and proliferation markers. Overall, these findings demonstrate that selective HDAC6 inhibition by Mesinostat modulates key oncogenic pathways in TNBC, supporting its potential as a promising therapeutic approach for HDAC6-overexpressing breast cancers.

三阴性乳腺癌（TNBC）仍然是最具侵袭性的乳腺癌亚型，占乳腺癌相关死亡人数的一半以上。在精准肿瘤学时代，表观遗传失调已成为乳腺肿瘤发生的关键驱动因素。在表观遗传靶点中，组蛋白去乙酰化酶6 （HDAC6）因其细胞质定位和调控非组蛋白底物如Hsp90、α-微管蛋白和内联蛋白而受到越来越多的关注。我们最近发现了一类新的螺旋环分子作为有效的和选择性的HDAC6抑制剂。在这里，我们研究了Mesinostat（该系列中最具选择性的化合物之一）在人类TNBC细胞系、3D球体和来自淋巴结转移的患者源性类器官（PDOs）中的药理学特征。在TNBC细胞中，使用western blot分析，我们证明Mesinostat（1-30µM）通过增加乙酰化α-微管蛋白水平选择性抑制HDAC6，而对组蛋白H3乙酰化没有影响。然而，Mesinostat通过凋亡、细胞周期阻滞和自噬显著降低细胞增殖。此外，它抑制上皮-间质转化，减少细胞迁移，破坏球体完整性。PDOs的治疗导致细胞活力和克隆生成能力的剂量依赖性降低，并伴有干性和增殖标志物的下调。总的来说，这些发现表明，Mesinostat选择性抑制HDAC6可调节TNBC中关键的致癌途径，支持其作为HDAC6过表达乳腺癌治疗方法的潜力。

{"title":"Selective HDAC6 inhibition by Mesinostat impairs tumor growth and stemness in triple-negative breast cancer","authors":"Ivana Bello , Simona Barone , Anna Guadagni, Camilla Esposito, Morena D’Ariano, Martina Smimmo, Giuseppe Cirino, Vincenzo Summa, Margherita Brindisi , Elisabetta Panza","doi":"10.1016/j.phrs.2025.108055","DOIUrl":"10.1016/j.phrs.2025.108055","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) remains the most aggressive breast cancer subtype, accounting for over half of breast cancer-related deaths. In the era of precision oncology, epigenetic dysregulation has emerged as a key driver of breast tumorigenesis. Among epigenetic targets, histone deacetylase 6 (HDAC6) has attracted increasing attention due to its cytoplasmic localization and regulation of non-histone substrates such as Hsp90, α-tubulin, and cortactin. We recently identified a novel class of spirocyclic molecules as potent and selective HDAC6 inhibitors. Here, we investigated the pharmacological profile of Mesinostat, one of the most selective compounds of this series, in human TNBC cell lines, 3D spheroids, and patient-derived organoids (PDOs) from lymph node metastases. In TNBC cells, using western blot analysis, we demonstrated that Mesinostat (1–30 µM) selectively inhibited HDAC6 by increasing acetylated α-tubulin levels, with no effect on the histone H3 acetylation. Yet, Mesinostat markedly reduced cell proliferation through apoptosis, cell cycle arrest, and autophagy. Furthermore, it inhibited epithelial-mesenchymal transition, decreased cell migration, and disrupted spheroid integrity. Treatment of PDOs led to a dose-dependent reduction in viability and clonogenic capacity, accompanied by downregulation of stemness and proliferation markers. Overall, these findings demonstrate that selective HDAC6 inhibition by Mesinostat modulates key oncogenic pathways in TNBC, supporting its potential as a promising therapeutic approach for HDAC6-overexpressing breast cancers.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108055"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Proteolysis targeting chimera degraders target pseudokinases to treat metabolic dysfunction-associated steatohepatitis and fibrosis: Mechanisms and therapeutic insights 靶向嵌合体降解物的蛋白水解靶向假激酶治疗代谢功能障碍相关的脂肪性肝炎和纤维化：机制和治疗见解。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108054

Yibing Wang , Jiajing Peng

Metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) is the severe type of metabolic dysfunction-associated steatotic liver disease (MASLD, previously NAFLD), the most common liver condition. The excessive hepatic lipid accumulation triggers apoptosis of hepatocytes and lobular inflammation, which are the key features of MASH. MASH may develop into liver fibrosis, while current therapeutics exhibit limited responses in patients. Identification of novel upstream regulators for both hepatic inflammation and fibrosis holds great promise to treat MASH and liver fibrosis. Pseudokinases, which contain the pseudokinase domains without kinase activity, are hub genes that integrate the signaling pathways of cell death, inflammation and fibrosis in the liver. We critically analyze the STAT and other signaling pathways through which JAK1, JAK2 (kinases with pseudokinase domains), TRIB2, MLKL and IRAK-M regulate the progression of MASH and liver fibrosis. Collectively, pseudokinases are potential therapeutic targets for treating MASH and liver fibrosis. Although the pseudokinase inhibitors show effectively treat inflammatory diseases, specific and safe pseudokinase inhibitors are understudied. Proteolysis targeting chimeras (PROTACs) are rapidly evolved bifunctional molecules that efficiently bind to and catalytically degrade the target proteins via recruiting E3 ubiquitin ligases. We discuss the design, selectivity, and limitations of pseudokinase PROTACs, and present the most active lead PROTACs that may treat MASH and liver fibrosis at distinct stages. Furthermore, innovative strategies enhance PROTACs’ efficacy through addressing the main translational hurdles, especially the low bioavailability and cellular uptake. It facilitates the development of PROTACs to probe in vivo function of pseudokinases and to combat MASH and liver fibrosis.

代谢功能障碍相关脂肪性肝炎（MASH，以前称为NASH）是代谢功能障碍相关脂肪性肝病（MASLD，以前称为NAFLD）的严重类型，是最常见的肝脏疾病。过度的肝脂质积累引发肝细胞凋亡和小叶炎症，这是MASH的主要特征。MASH可能发展为肝纤维化，而目前的治疗方法对患者的反应有限。鉴定出肝脏炎症和纤维化的新型上游调节因子对治疗MASH和肝纤维化具有很大的希望。假激酶是整合肝脏细胞死亡、炎症和纤维化信号通路的枢纽基因，它包含无激酶活性的假激酶结构域。我们批判性地分析了STAT和其他JAK1， JAK2（具有假激酶结构域的激酶），TRIB2， MLKL和IRAK-M调节MASH和肝纤维化进展的信号通路。总的来说，假激酶是治疗MASH和肝纤维化的潜在治疗靶点。虽然假激酶抑制剂能有效治疗炎症性疾病，但特异性和安全性的假激酶抑制剂还有待研究。蛋白水解靶向嵌合体（Proteolysis targeting chimeras, PROTACs）是一种快速进化的双功能分子，通过招募E3泛素连接酶有效结合并催化降解靶蛋白。我们讨论了假激酶PROTACs的设计、选择性和局限性，并提出了可能在不同阶段治疗MASH和肝纤维化的最活跃的PROTACs导联。此外，创新策略通过解决主要的转化障碍，特别是低生物利用度和细胞摄取来提高PROTACs的功效。它促进了PROTACs的发展，以探测假激酶的体内功能，并对抗MASH和肝纤维化。

{"title":"Proteolysis targeting chimera degraders target pseudokinases to treat metabolic dysfunction-associated steatohepatitis and fibrosis: Mechanisms and therapeutic insights","authors":"Yibing Wang , Jiajing Peng","doi":"10.1016/j.phrs.2025.108054","DOIUrl":"10.1016/j.phrs.2025.108054","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) is the severe type of metabolic dysfunction-associated steatotic liver disease (MASLD, previously NAFLD), the most common liver condition. The excessive hepatic lipid accumulation triggers apoptosis of hepatocytes and lobular inflammation, which are the key features of MASH. MASH may develop into liver fibrosis, while current therapeutics exhibit limited responses in patients. Identification of novel upstream regulators for both hepatic inflammation and fibrosis holds great promise to treat MASH and liver fibrosis. Pseudokinases, which contain the pseudokinase domains without kinase activity, are hub genes that integrate the signaling pathways of cell death, inflammation and fibrosis in the liver. We critically analyze the STAT and other signaling pathways through which JAK1, JAK2 (kinases with pseudokinase domains), TRIB2, MLKL and IRAK-M regulate the progression of MASH and liver fibrosis. Collectively, pseudokinases are potential therapeutic targets for treating MASH and liver fibrosis. Although the pseudokinase inhibitors show effectively treat inflammatory diseases, specific and safe pseudokinase inhibitors are understudied. Proteolysis targeting chimeras (PROTACs) are rapidly evolved bifunctional molecules that efficiently bind to and catalytically degrade the target proteins via recruiting E3 ubiquitin ligases. We discuss the design, selectivity, and limitations of pseudokinase PROTACs, and present the most active lead PROTACs that may treat MASH and liver fibrosis at distinct stages. Furthermore, innovative strategies enhance PROTACs’ efficacy through addressing the main translational hurdles, especially the low bioavailability and cellular uptake. It facilitates the development of PROTACs to probe <em>in vivo</em> function of pseudokinases and to combat MASH and liver fibrosis.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108054"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Effect of esketamine on postoperative depression and anxiety in patients undergoing cardiac valve surgery: A randomised, placebo-controlled, double-blinded clinical trial 艾氯胺酮对心脏瓣膜手术患者术后抑郁和焦虑的影响：一项随机、安慰剂对照、双盲临床试验

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108047

Zhuo-Ning Zhang , Xin-Yu Hao , Chen Cai , Li Sun , Zi-Yi Zhang , Miao Wang , Yi-Shuang Wu , Ying Wang , Jiang-Bei Cao , Yan-Hong Liu , Jing-Sheng Lou , Qiang Fu , Sheng-Li Jiang , Ru-Quan Han , Wei-Dong Mi , Li Tong

This randomized, double-blind, parallel-group trial evaluated the efficacy of a single intravenous dose of esketamine (0.3 mg/kg) administered at anesthesia induction in reducing postoperative depression and anxiety among patients undergoing cardiac valve surgery. A total of 142 patients from three centers were randomly assigned to receive esketamine or saline. The primary outcomes were the prevalence of depression and anxiety at postoperative day (POD) 7, assessed by the Hospital Anxiety and Depression Scale (HADS). Key secondary outcomes included delirium incidence, pain and insomnia scores, and quality of recovery. Results showed that the esketamine group had significantly lower rates of depression (7.0 % vs. 31.0 %; P < 0.001) and anxiety (11.3 % vs. 35.2 %; P < 0.001) at POD 7, along with reduced delirium incidence (9.8 % vs. 22.5 %; P = 0.040). Improvements were also observed in pain, sleep, and recovery quality. Mechanistic analyses revealed that esketamine reduced inflammatory markers (IL-6, CRP) and neuronal injury marker (S100β), while increasing brain-derived neurotrophic factor (BDNF). No significant differences in adverse events were observed. In conclusion, a single low dose of esketamine during induction effectively alleviates early postoperative depression and anxiety, possibly through modulating neuroinflammation and promoting neurotrophic signaling. (Clinicaltrials.gov, ID Number: NCT06608030).

这项随机、双盲、平行组试验评估了麻醉诱导时单次静脉注射艾氯胺酮（0.3mg/kg）减轻心脏瓣膜手术患者术后抑郁和焦虑的疗效。来自三个中心的142名患者被随机分配接受艾氯胺酮或生理盐水治疗。主要结局是术后当天抑郁和焦虑的发生率（POD） 7，由医院焦虑和抑郁量表（HADS）评估。主要的次要结局包括谵妄发生率、疼痛和失眠评分以及恢复质量。结果显示，艾氯胺酮组抑郁发生率明显低于对照组(7.0% vs. 31.0%

{"title":"Effect of esketamine on postoperative depression and anxiety in patients undergoing cardiac valve surgery: A randomised, placebo-controlled, double-blinded clinical trial","authors":"Zhuo-Ning Zhang , Xin-Yu Hao , Chen Cai , Li Sun , Zi-Yi Zhang , Miao Wang , Yi-Shuang Wu , Ying Wang , Jiang-Bei Cao , Yan-Hong Liu , Jing-Sheng Lou , Qiang Fu , Sheng-Li Jiang , Ru-Quan Han , Wei-Dong Mi , Li Tong","doi":"10.1016/j.phrs.2025.108047","DOIUrl":"10.1016/j.phrs.2025.108047","url":null,"abstract":"<div><div>This randomized, double-blind, parallel-group trial evaluated the efficacy of a single intravenous dose of esketamine (0.3 mg/kg) administered at anesthesia induction in reducing postoperative depression and anxiety among patients undergoing cardiac valve surgery. A total of 142 patients from three centers were randomly assigned to receive esketamine or saline. The primary outcomes were the prevalence of depression and anxiety at postoperative day (POD) 7, assessed by the Hospital Anxiety and Depression Scale (HADS). Key secondary outcomes included delirium incidence, pain and insomnia scores, and quality of recovery. Results showed that the esketamine group had significantly lower rates of depression (7.0 % vs. 31.0 %; P < 0.001) and anxiety (11.3 % vs. 35.2 %; P < 0.001) at POD 7, along with reduced delirium incidence (9.8 % vs. 22.5 %; P = 0.040). Improvements were also observed in pain, sleep, and recovery quality. Mechanistic analyses revealed that esketamine reduced inflammatory markers (IL-6, CRP) and neuronal injury marker (S100β), while increasing brain-derived neurotrophic factor (BDNF). No significant differences in adverse events were observed. In conclusion, a single low dose of esketamine during induction effectively alleviates early postoperative depression and anxiety, possibly through modulating neuroinflammation and promoting neurotrophic signaling. (Clinicaltrials.gov, ID Number: NCT06608030).</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108047"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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