Biochemical pharmacology最新文献

{"title":"Icaritin enhances the antitumor efficacy of irinotecan by dual-targeting carboxylesterase 2 and p53 in vitro and in vivo","authors":"Jiahui Zhang ,&nbsp;Yaojun Wang ,&nbsp;Chunlai Yin ,&nbsp;Xiangyu Shi ,&nbsp;Zujia Chen ,&nbsp;Yingying Wang ,&nbsp;Yueyue Li ,&nbsp;Changyuan Wang ,&nbsp;Jie Li ,&nbsp;Jingjing Wu ,&nbsp;Yongshun Zhao","doi":"10.1016/j.bcp.2026.117777","DOIUrl":"10.1016/j.bcp.2026.117777","url":null,"abstract":"<div><div>Carboxylesterase 2 (CES2), a member of the serine hydrolase superfamily, plays a crucial role in catalyzing the hydrolysis of numerous endogenous and exogenous compounds containing ester bonds. The commonly used clinical drug irinotecan (CPT-11) exerts its anti-tumor effect by being hydrolyzed by CES2 to generate SN-38. Epimedium, a widely used traditional Chinese herb with multiple pharmacological properties, has not yet been characterized for its effects on CES2. Our study systematically evaluated the three principal bioactive components of Epimedium for their effects on CES2 activity, revealing that icaritin significantly activated this enzyme. <em>In vitro</em>, Western blot and RT-PCR assays demonstrated that icaritin significantly upregulated CES2 expression at both mRNA and protein levels. Furthermore, icaritin further enhanced CES2 expression by activating the PXR pathway and increased the protein level of P53. Molecular docking simulations demonstrated that the interation energy between CES2 and icaritin was significantly higher than that with cisplatin (a reported CES2 activator), which might suggest that CES2 has a higher affinity for icaritin than cisplatin. <em>In vivo</em> studies confirmed that icaritin increased the hydrolytic activity and protein expression of Ces in mouse liver and intestinal tissues with a concentration-dependent manner. In conclusion, icaritin can enhance the hydrolysis of irinotecan in vitro and in vivo, and this enhancement is related to the activation of CES2 and the increase of CES2 gene and protein expression. These findings have important clinical significance for reducing chemotherapy drug resistance in cancer patients.</div><div>Abbreviations: CES2, Carboxylesterase 2; CRC, Colorectal cancer; CPT-11, Irinotecan; CYP3A, Cytochrome P450 3A; NR, Nuclear receptor; P53, Tumor protein p53; PPAR-α, Peroxisome proliferator-activated receptor α; PXR, Pregnane X receptor; SN-38, 7-Ethyl-10-hydroxycamptothecin; UGT1A1, UDP-glucuronosyltransferase 1A1.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117777"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137154","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}

{"title":"U07, a novel oridonin derivative, targets polo-like kinase 4 (PLK4) to induce ferroptosis in gastric cancer cells","authors":"Yingpeng Huang ,&nbsp;Yujie Lin ,&nbsp;Qishuo Zhou ,&nbsp;Yingqi Liang ,&nbsp;Mingdong Lu ,&nbsp;Fang Wu ,&nbsp;Qiantong Dong ,&nbsp;Jun Cheng","doi":"10.1016/j.bcp.2026.117774","DOIUrl":"10.1016/j.bcp.2026.117774","url":null,"abstract":"<div><div>This study aimed to systematically investigate the inhibitory effect and potential molecular mechanism of oridonin derivative U07 on gastric cancer cells. By combining in vitro cell experiments and in vivo animal experiments, techniques including Cell Counting Kit-8 (CCK-8) assay, colony formation assay, Annexin V-FITC/Propidium Iodide (Annexin V/PI) double-staining flow cytometry, Western blot, wound healing assay, Transwell invasion assay, fluorescence staining, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and molecular docking were used to analyze the impact of U07 on the biological behavior of gastric cancer cells and related molecular pathways. The results showed that U07 exhibited concentration-dependent cytotoxicity against HGC-27 and MKN-45 gastric cancer cells (with IC₅₀ values of 2.5 μM and 2.6 μM, respectively). It could inhibit cell proliferation and induce apoptosis by activating the caspase-3 pathway, while significantly reducing cell migration and invasion abilities. U07 concentration-dependently increased the levels of reactive oxygen species (ROS) and lipid peroxidation, decreased glutathione (GSH) content, and increased malondialdehyde (MDA) content, thereby triggering ferroptosis; this effect could be blocked by the ferroptosis inhibitor Fer-1. Molecular studies confirmed that U07 could specifically bind to PLK4 kinase (KD = 6.2 μM detected by SPR, Kd = 0.65 μM detected by ITC) and inhibit its activity. PLK4 negatively regulates frroptosis pathway by directly binding to and transcriptionally activating Glutathione Peroxidase 4 (GPX4) / ferritin heavy chain 1 (FTH1). By downregulating PLK4, U07 further reduced the expression of ferroptosis marker proteins GPX4 and FTH1, and promoted lipid peroxidation and ROS production; however, overexpression of PLK4 could reverse these effects. In vivo experiments demonstrated that U07 could inhibit tumor growth in a dose-dependent manner, with the high-dose group (6 mg) showing an anti-tumor effect comparable to that of cisplatin, and it could downregulate the expression of PLK4 and GPX4 in tumor tissues. In conclusion, the oridonin derivative U07 exerts anti-gastric cancer effects by inhibiting cell proliferation, inducing apoptosis, and mediating ferroptosis via PLK4, providing a new candidate drug and therapeutic target for gastric cancer treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117774"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140925","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}

{"title":"Eurycomanol alleviates hyperuricemia-induced cortisol disorders by upregulating SRD5A1 via IKKβ-IκBα-NF-κB-DNMT pathway","authors":"Jujie Pan ,&nbsp;Ruixia Bao ,&nbsp;Qian Chen ,&nbsp;Yuzheng Wu ,&nbsp;Beibei Chen ,&nbsp;Zicheng Zhu ,&nbsp;Jing Xie ,&nbsp;Yi Zhang ,&nbsp;Tao Wang ,&nbsp;Dan Wang","doi":"10.1016/j.bcp.2026.117787","DOIUrl":"10.1016/j.bcp.2026.117787","url":null,"abstract":"<div><div>Hyperuricemia (HUA) is a chronic metabolic disease which has been previously observed to be associated with cortisol metabolism disorders (pseudohypoadrenalism). In this study, we aimed to investigate the efficacy as well as mechanism of <em>Eurycoma longifolia</em> Jack (TkA) on alleviating cortisol metabolism. Oral administration of TkA significantly decreased serum uric acid levels and urinary cortisol in HUA mice. TkA improved HPA axis function and upregulated the levels of adrenal <em>Hsd3b2</em>, <em>Cyp21a1</em> and <em>Cyp11b1</em>. In the liver, TkA upregulated the expression of <em>Srd5a1</em> and <em>Akr1c4</em>, promoting the conversion from cortisol to 5α-tetrahydrocortisol (<em>P</em> &lt; 0.001). TNFα was found to be the principal driver of reduced SRD5A1. By activating NF-κB pathway, recruited DNA methyltransferase (DNMT) binding with the CpG islands increased methylation level of <em>Srd5a1</em>. Our findings highlight that eurycomanol significantly inhibited the activation of IKKβ/IκBα/NF-κB/DNMT pathway as well as up-regulated hepatic SRD5A1, thereby restoring the systemic cortisol metabolic homeostasis under HUA.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117787"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163942","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}

{"title":"Treatment with anti-Hsp90 antibody mitigates fibronectin-related cardiac fibrosis induced by pressure overload in mice","authors":"Tetsuro Marunouchi,&nbsp;Takuma Murakami,&nbsp;Kano Yamaguchi,&nbsp;Kotone Hiraga,&nbsp;Haruka Ban,&nbsp;Kouichi Tanonaka","doi":"10.1016/j.bcp.2026.117780","DOIUrl":"10.1016/j.bcp.2026.117780","url":null,"abstract":"<div><div>Heart failure is a chronic condition with a poor prognosis, and the development of new treatments is an urgent necessity. Extracellular heat shock protein 90 (eHsp90) has been observed to increase in heart failure. However, the pathophysiological role of extracellular Hsp90 (eHsp90) in heart failure development remains unclear. Thus, this study aimed to examine the effects of the anti-Hsp90 antibody 1G6-D7, an eHsp90 inhibitor, on cardiac fibrosis induced by pressure overload. Eight-week-old male C57Bl/6N mice underwent transverse aortic constriction (TAC). Beginning 2 <!--> <!-->weeks after surgery, the anti-Hsp90 antibody or normal IgG was administered intravenously every 2 weeks. Mice treated with normal IgG developed chronic heart failure with severe myocardial fibrosis 8 weeks after TAC. By contrast, administration of the anti-Hsp90 antibody to the TAC mice partially attenuated myocardial fibrosis and improved cardiac function. The fibronectin level in the myocardial tissue and the interaction between Hsp90 and fibronectin increased in the TAC mice treated with normal IgG. Conversely, these pathophysiological changes were mitigated in the TAC mice treated with the anti-Hsp90 antibody. The results of this study suggest that eHsp90 contributes to cardiac fibrosis by mediating fibronectin in the extracellular space. Furthermore, treatment with the anti-Hsp90 antibody attenuated cardiac fibrosis, which is associated with decreased fibronectin levels. The results of this study indicate eHsp90 as a novel extracellular target molecule for treating heart failure. In addition, our findings also suggested that anti-Hsp90 antibody hold considerable promise as potential pharmaceutical agents for the treatment of heart failure by targeting eHsp90.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117780"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148954","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}

{"title":"Oxidative stress in metabolic dysfunction-associated steatohepatitis: Mechanisms and emerging therapeutic strategies","authors":"Yidan Chen,&nbsp;Hui Yu,&nbsp;Xinyu Kai,&nbsp;Runting Yin,&nbsp;Zhen Ouyang,&nbsp;Yuan Wei,&nbsp;Cai Zhang","doi":"10.1016/j.bcp.2026.117702","DOIUrl":"10.1016/j.bcp.2026.117702","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), affect a substantial proportion of the global population and have emerged as a major disease burden. If left untreated, MASH can progress to cirrhosis and hepatocellular carcinoma. However, effective pharmacological therapies for MASH remain limited. Accumulating evidence indicates that oxidative stress plays an important role in MASH pathogenesis by coordinating inflammatory responses and contributing to hepatocyte injury. Although previous studies have emphasized the importance of oxidative stress, a panoramic view of how oxidative stress emerges during the onset of MASH and sustains a vicious cycle of progression is still lacking. This review systematically discusses the mechanisms underlying oxidative stress-driven MASH progression, highlighting its interactions with inflammation, hepatocyte apoptosis, necroptosis, emerging ferroptosis, and mitochondria-associated membranes. Furthermore, we summarize the recent advances in investigational drugs targeting oxidative stress, encompassing key druggable targets as well as representative synthetic compounds, natural products, and biotechnology drugs. Collectively, this review aims to deepen the mechanistic understanding of oxidative stress in MASH and to provide insights into potential therapeutic strategies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117702"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958597","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}

{"title":"Extracellular vesicles are a double-edged sword in cardiac fibrosis: an epigenetic perspective","authors":"Peng Liu ,&nbsp;Zhen-Yu Liu ,&nbsp;Sui Mao ,&nbsp;Li-Chan Lin ,&nbsp;Ye Zhang ,&nbsp;Jian-Yuan Zhao ,&nbsp;Hui Tao","doi":"10.1016/j.bcp.2026.117743","DOIUrl":"10.1016/j.bcp.2026.117743","url":null,"abstract":"<div><div>Cardiac fibrosis is regarded as a central mechanism by which different cardiovascular diseases react to a range of pathophysiological stimuli. The key features of cardiac fibrosis include the activation of fibroblasts, abnormal cellular proliferation, excessive extracellular matrix deposition, and an altered distribution of matrix components. As research on cardiac fibrosis advances, it has become increasingly clear that extracellular signals play a crucial role in regulating its initiation and progression. Hence, extracellular vesicles serve as pivotal mediators in intercellular communication, facilitating the transmission of a multitude of epigenetic signals and the conveyance of specific gene expression regulatory factors, thereby exerting a modulating influence on the development of cardiac fibrosis. Extracellular vesicles exhibit a dual role in cardiac fibrosis progression, as they can either promote or inhibit the fibrotic process. This review thoroughly explores the epigenetic regulatory mechanisms of extracellular vesicles (EVs) in mediating the process of cardiac fibrosis, and analyzes potential therapeutic intervention strategies. The research results indicate that extracellular vesicles have significant potential for treating cardiac fibrosis through epigenetic regulation, providing an important theoretical basis for the treatment and clinical application of related diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117743"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040177","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}

{"title":"Integrative analyses of network pharmacology and bioinformatics reveal the synergistic antitumor effects of cantharidin and ginsenosides Rg3 on hepatocellular carcinoma","authors":"Xianggang Gou ,&nbsp;Zhongzheng Zhou ,&nbsp;Yuehua Wang ,&nbsp;Henye Yuan ,&nbsp;Ziyao Wang ,&nbsp;Jie Chen ,&nbsp;Wei Yan ,&nbsp;Haisheng Wang ,&nbsp;Jia Yan","doi":"10.1016/j.bcp.2026.117700","DOIUrl":"10.1016/j.bcp.2026.117700","url":null,"abstract":"<div><div>Cantharidin (CTD) has been traditionally used in Traditional Chinese Medicine (TCM) and exhibits pronounced antitumor activity, particularly in hepatocellular carcinoma (HCC). However, its preclinical translation has been substantially constrained by dose-limiting toxicity. Inspired by traditional <em>Mylabris</em> and <em>Ginseng</em> combinations, we conducted an investigation into the synergistic efficacy of CTD and Ginsenoside-Rg3 (Rg3), one of the most prevalent and bioactive ginsenosides, in combating HCC. We find that CTD/Rg3 co-treatment synergistically suppressed HCC cell proliferation, migration, and invasion. Mechanistically, an integrated multi-omics approach analyses illuminated the involvement of multi-target and multi-pathway mechanisms in CTD/Rg3 combination therapy for HCC. Function enrichment analyses reveal that targets of CTD/Rg3 were significantly associated with metabolic pathways and immune responses. Further screening identified AKR1D1, SLC16A4, and ALDH3B1 as potential drug targets. Subsequent correlation analysis with clinical data from liver cancer patients indicated that AKR1D1 and SLC16A4 were activated, whereas ALDH3B1 was inhibited, during CTD/Rg3 intervention in HCC progression. Molecular docking studies further demonstrated that both CTD and Rg3 bind with high affinity and stability to the active site of ALDH3B1, a molecule associated with immune microenvironment remodeling in HCC. Collectively, our findings demonstrate that CTD/Rg3 combination therapy exerts potent anti-HCC effects through multi-targeted mechanisms. By simultaneously modulating metabolic pathways and immune responses, this strategy represents a novel integrative approach for HCC treatment. These results not only elucidate the molecular basis of CTD/Rg3 efficacy but also provide robust preclinical support for its clinical translation in HCC management.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117700"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951268","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}

{"title":"Unraveling the glioblastoma (GBM) tumor microenvironment: future perspective on targeted immunotherapy","authors":"Jia Li ,&nbsp;Abdulkareem Qasem Moqbel ,&nbsp;Yongzhao Wang ,&nbsp;Erhu Zhao ,&nbsp;Muhammad Usman Ghani ,&nbsp;Ping Liang","doi":"10.1016/j.bcp.2026.117724","DOIUrl":"10.1016/j.bcp.2026.117724","url":null,"abstract":"<div><div>Glioblastoma (GBM) is one of the most aggressive, fast-growing, and therapeutically challenging brain tumors. The difficulty in managing GBM stems from its genetic instability and the intricately complex tumor microenvironment (TME). Within the TME, intricate interactions between neoplastic cells and signaling mediators drive tumor progression. Despite advances in current treatments, obstacles such as the blood–brain barrier (BBB) and pronounced inter- and intratumoral heterogeneity continue to hinder therapeutic success. Consequently, research efforts have increasingly focused on immunotherapeutic strategies that combine immune checkpoint inhibitors (ICIs) with standard-of-care (SOC) treatments or other immune-remodeling modalities, which seek to reprogram the tumor landscape and restore robust, durable anti-tumor responses. In this context, chemoradiation and oncolytic viruses induce immunogenic cell death and activate innate immunity, creating opportunities for checkpoint inhibitors to amplify T-cell responses. Complementing these strategies, engineered CAR-T cells and myeloid-targeting agents address tumor antigen loss and macrophage-mediated suppression of the immune response. Together, by targeting these complementary resistance mechanisms, combination regimens hold the potential to transform the immunologically ‘cold’ GBM TME into an inflamed and treatment-responsive state. Collectively, these combinatorial approaches converge to remodel the GBM microenvironment, enhancing dendritic cell (DC) activation, promoting T-cell infiltration, and thereby promoting durable anti-tumor immunity, as well as extending survival. This review provides a comprehensive analysis of the TME’s role in GBM progression, highlighting the latest immunotherapeutic advances designed to address TME-related obstacles and enhance therapeutic efficacy and patient survival.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117724"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028357","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}

{"title":"Arachidonic acid analog AACOCF3 suppresses cPLA2-negative NSCLC cell proliferation by targeting SSRP1 to activate the IFNα/β pathway","authors":"Hongbo Wang ,&nbsp;Zihao Wen ,&nbsp;Yupeng Jia ,&nbsp;Xinyu Tong ,&nbsp;Weifang Wang ,&nbsp;Ze Wang ,&nbsp;Hongkai Jin ,&nbsp;Xiaoya Gao ,&nbsp;Xinyuan Tao ,&nbsp;Hao Cheng ,&nbsp;Tingting Li ,&nbsp;Shinan Li ,&nbsp;Tingting Chen ,&nbsp;Kunfang Li ,&nbsp;Bo Li","doi":"10.1016/j.bcp.2026.117708","DOIUrl":"10.1016/j.bcp.2026.117708","url":null,"abstract":"<div><div>AACOCF3, a cell-permeable arachidonic acid analogue, is widely established as a selective inhibitor of cytosolic phospholipase A2 (cPLA2, PLA2G4A) in studies of metabolic disorders. Although its primary mechanism involves cPLA2 inhibition, emerging evidence indicates that AACOCF3 may target additional protein entities, exemplified by calcium-independent phospholipase A2 (iPLA2, PLA2G6) and fatty acid amide hydrolase (FAAH). Notably, cPLA2 displays a markedly heterogeneous expression profile in non-small cell lung cancer (NSCLC). Our findings establish that AACOCF3 exerts more potent growth inhibition in cPLA2-negative NSCLC cells, with IC50 values of 15.13 μM for H1975 and 15.84 μM for PC9 cells, in contrast to the cPLA2-positive A549 cells (IC50 = 56.23 μM). Mechanistically, AACOCF3 upregulates IFN-α/β signaling-associated genes (e.g., <em>IFNB1, ISG15</em>) specifically in cPLA2-negative NSCLC cells. This aligns with TCGA-LUAD data revealing that PLA2G4A-low tumors predominantly engage immune-activation pathways rather than metabolic programs when compared to PLA2G4A-high counterparts. Through integrated molecular docking and surface plasmon resonance (SPR) analysis, we identified structure-specific recognition protein 1 (SSRP1) as a direct molecular target of AACOCF3 in cPLA2-negative NSCLC, with SPR binding studies confirming a stable interaction (Kd = 25.9 μM). Ectopic SSRP1 expression abrogated AACOCF3-induced phenotypic alterations, concurrently suppressing IFN-α/β signaling. Collectively, these results provide evidence that AACOCF3 exerts its anti-proliferative effect by targeting SSRP1, which leads to the activation of the IFNα/β pathway, thereby underscoring its therapeutic promise for the cPLA2-negative patient subpopulation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117708"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987859","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}

{"title":"Development of an UPLC-MS/MS method for quantification of donafenib and its metabolite in rat plasma: application to drug–drug interaction","authors":"Yuxin Shen ,&nbsp;Ruibin Li ,&nbsp;Lu Cao ,&nbsp;Jun Wu ,&nbsp;Haoxin Fu ,&nbsp;Peiqi Wang ,&nbsp;Ren-ai Xu ,&nbsp;Ling Ji","doi":"10.1016/j.bcp.2025.117540","DOIUrl":"10.1016/j.bcp.2025.117540","url":null,"abstract":"<div><div>Donafenib is a deuterated drug used as a first-line treatment for unresectable hepatocellular carcinoma (HCC). And efavirenz is an antiretroviral for human immunodeficiency virus (HIV) treatment. Due to the high prevalence of HCC in HIV patients, the combination of the two drugs is increasingly common. This study developed an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for simultaneous quantitative determination of donafenib and its metabolite donafenib N-oxide, and assessed the impact of efavirenz on donafenib metabolism. In this bioanalytical method, good linearity (<em>r</em>² = 0.99) was observed for donafenib (5–40,000 ng/mL) and donafenib N-oxide (2–400 ng/mL), with lower limit of quantification (LLOQ) of 5 ng/mL and 2 ng/mL, respectively. The precision (RSD%) and accuracy (RE%) of both compounds were less than ±15 %. In addition, the results of recovery, matrix effect, and stability were all in accordance with FDA guidelines. <em>In vitro</em>, efavirenz inhibited the metabolism of donafenib in rat liver microsomes (RLM) and human liver microsomes (HLM) with the half-maximum inhibitory concentration (IC₅₀) values of 5.87 μM and 39.14 μM, respectively, with no time-dependent inhibition (TDI). Moreover, the mechanism of inhibition was a mixture type in RLM. <em>In vivo</em>, the AUC_(0-t), AUC_(0-∞) and C_max of donafenib and donafenib N-oxide were significantly increased in the presence of efavirenz, which indicated that efavirenz increased the exposure of donafenib in rats. In short, this UPLC-MS/MS method was reliable for quantifying donafenib and its metabolite, and the findings suggested that efavirenz had an inhibitory effect on the metabolism of donafenib <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117540"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530460","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}