Biochemical pharmacology最新文献

{"title":"METTL3-m6A-MALAT1 axis exacerbates the autophagy impairment and lipid accumulation in NAFLD by regulating miR-690","authors":"Guowei Zhu ,&nbsp;Junqing Yang ,&nbsp;Dongzhi Ran ,&nbsp;Ying Luo ,&nbsp;Yanyi Wang ,&nbsp;Wenjia Guo ,&nbsp;Xiaodan Tan ,&nbsp;Xiaobing Zhao ,&nbsp;Yuanhong Gan ,&nbsp;Huafeng Yin ,&nbsp;Hong Wang","doi":"10.1016/j.bcp.2026.117806","DOIUrl":"10.1016/j.bcp.2026.117806","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) has become the fastest-growing etiology of cirrhosis and hepatocellular carcinoma. No Food and Drug Administration (FDA)-approved pharmacotherapy currently exists, underscoring the urgent need for novel regulatory circuits that can be translated into druggable targets. Here we demonstrate that autophagic flux is severely impaired and lipid accumulation markedly exacerbated in livers of NAFLD mouse models and in hepatocytes challenged with free fatty acid (FFA). Knock-down of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) elevated miR-690 abundance, restored autophagic flux, and attenuated intracellular lipid deposition. Consistently, silencing methyltransferase-like 3 (METTL3) decreased MALAT1, thereby increasing miR-690 and producing the same protective phenotype, whereas METTL3 over-expression elicited the opposite effects. Mechanistically, METTL3 directly bound MALAT1 and installed N6-methyladenosine (m6A) modifications that enhanced MALAT1 stability and expression. Up-regulated MALAT1 subsequently sponged miR-690, leading to its functional depletion, autophagosome–lysosome fusion blockade, and aggravated lipid retention. Collectively, the METTL3-m6A/MALAT1/miR-690 axis orchestrates autophagy and lipid homeostasis, operationalizing an “m6A–long non-coding RNA (lncRNA)–microRNA (miRNA)” regulatory paradigm in NAFLD and offering an epitranscriptomic perspective on disease pathogenesis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117806"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197388","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":"Genkwanin enhances survival of rat random skin flap: promoting autophagic flux by modulation of AMPK/TSC2/mTOR signaling pathway through SIRT1","authors":"Jian-xiong Zhang ,&nbsp;Yang-bo Li ,&nbsp;Jian-peng Lu ,&nbsp;Jia-di Le ,&nbsp;Zheng-hao Wu ,&nbsp;Yang-can Jin ,&nbsp;Si-yuan Chen ,&nbsp;Le-yi Cai ,&nbsp;Long Chen","doi":"10.1016/j.bcp.2026.117797","DOIUrl":"10.1016/j.bcp.2026.117797","url":null,"abstract":"<div><div>Large scale skin defects and skin reconstruction require the use of random skin flaps, and the size and shape of the flaps can be designed according to the wound. However, distal ischemic necrosis of random skin flaps is a major challenge after transplantation. The purpose of this study is to investigate the role of Genkwanin (GE) in ischemic necrosis of random skin flaps. Network pharmacology predicted the potential target SIRT1 and related pathways (including AMPK/TSC2 pathway) of GE. Transcriptomic sequencing further elucidated the mechanism of GE action. On postoperative day 7, skin flap survival was grossly evaluated, and laser Doppler imaging, Western blot analysis, histochemistry, and immunofluorescence all confirmed that GE enhanced autophagic flux. Moreover, autophagic flux exerted antioxidant, anti-apoptotic, and pro-angiogenic effects, ultimately increasing the flap survival rate. Even in the presence of H₂O₂, transwell, tube formation assays and other in vitro experiments such as cell fluorescence have shown that GE can still promote angiogenesis in HUVECs, accelerate cell proliferation rate, and reduce oxidative stress levels. Findings reveal GE enhances flap survival via SIRT1/AMPK/TSC2/mTOR -mediated enhancement of autophagic flux, offering a novel therapeutic strategy for ischemic tissue repair.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117797"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171737","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":"Genetic variants of flavin-containing monooxygenase (FMO) 1 and FMO3 in 5887 dogs influenced oxygenations of probe substrates benzydamine, trimethylamine, and methyl p-tolyl sulfide","authors":"Yasuhiro Uno ,&nbsp;Koya Fukunaga ,&nbsp;Makiko Shimizu ,&nbsp;Genki Ushirozako ,&nbsp;Keijiro Mizukami ,&nbsp;Tomomi Aoi ,&nbsp;Hirotaka Tomiyasu ,&nbsp;Muneki Honnami ,&nbsp;Hajime Tsujimoto ,&nbsp;Masahiro Sakaguchi ,&nbsp;Masaharu Hisasue ,&nbsp;Taisei Mushiroda ,&nbsp;Yukihide Momozawa ,&nbsp;Hiroshi Yamazaki","doi":"10.1016/j.bcp.2026.117790","DOIUrl":"10.1016/j.bcp.2026.117790","url":null,"abstract":"<div><div>NADPH-dependent flavin-containing monooxygenases (FMOs; EC 1.14.13.8) mediate the oxygenation of various <em>N</em>- or <em>S</em>-containing molecules. Human FMO1 and FMO3 metabolize the substrates benzydamine, trimethylamine, and methyl <em>p</em>-tolyl sulfide in the kidney and liver, respectively. FMO genetic variants contribute to variability in metabolic activity among individuals. However, genetic variants in dogs used in drug metabolism studies remain largely unexplored. In the present study, 5887 dog genomes were sequenced, and four nonsynonymous <em>FMO1</em> variants p.[(E45Q)], p.[(C159S)], p.[(F160Y)], and p.[(V234L)] and three nonsynonymous <em>FMO3</em> variants p.[(D253V)], p.[(P358S)], and p.[(P448L)] were identified. One frameshift <em>FMO3</em> variant c.116delG (p.[(G39Afs*28)]) was found, which is likely a null allele. Long-read sequencing identified three dog <em>FMO1</em> and four dog <em>FMO3</em> haplotypes. FMO1 variant p.[(C159S; F160Y)], which had a relatively high allele frequency in dogs, was recombinantly expressed in <em>Escherichia coli</em> membranes and found to have activities similar to those of the wild-type protein for the oxygenation of probe substrates. Recombinant FMO1 p.[(E45Q; C159S; F160Y)] exhibited similar benzydamine <em>N</em>-oxygenation and methyl <em>p</em>-tolyl sulfide <em>S</em>-oxygenation activities but significantly lower trimethylamine <em>N</em>-oxygenation activities than those of wild-type FMO1. FMO1 p.[(V234L)] exhibited probe oxygenation activities similar to those of wild-type FMO1. FMO3 p.[(D253V)], p.[(P358S)], and p.[(P448L)] variants showed significantly lower activities (approximately half) for <em>N-</em>oxygenation of benzydamine and trimethylamine and <em>S</em>-oxygenation of methyl <em>p</em>-tolyl sulfide than the FMO3 wild-type at substrate concentrations of 50 and/or 1000 µM. These results suggest that genetic variants of FMO1 and FMO3 may contribute to the variability in drug metabolism in dogs.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117790"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171739","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":"Cobrotoxin mitigates neuroinflammation and cognitive impairment by suppressing CD8+ T cell–microglia interactions in male 5 × FAD mice","authors":"Zhe Li ,&nbsp;Boyuan Tan ,&nbsp;Kaikai Dong ,&nbsp;Xinyue Yu ,&nbsp;Sophia W. Zhang ,&nbsp;Lin Luo ,&nbsp;Wenjuan Yao ,&nbsp;Zhenghong Qin ,&nbsp;Feng Wu","doi":"10.1016/j.bcp.2026.117779","DOIUrl":"10.1016/j.bcp.2026.117779","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline accompanied by chronic neuroinflammation. Emerging evidence implicates T-cell infiltration and microglial activation as key immune events that accelerate AD pathology, yet therapeutic approaches targeting this neuroimmune interface remain scarce. Cobrotoxin (CTX), a short-chain neurotoxin derived from <em>Naja atra</em> venom, exhibits potent anti-inflammatory and immunomodulatory properties and is clinically approved in China for the treatment of chronic pain syndromes. Here, we investigated whether CTX could alleviate neuroinflammation and cognitive deficits in 5 × FAD mice, a transgenic model of AD. Intranasal CTX administration for nine weeks enhanced spatial learning and memory in the Morris water maze without altering amyloid-β burden. Flow cytometry and immunofluorescence revealed that CTX markedly reduced brain-infiltrating CD8⁺ T cells and downregulated chemokines implicated in T cell–microglia communication, including Cxcl9, Cxcl10, Cxcl16, and Ccl5. Consistent with this, CTX attenuated microglial activation and pro-inflammatory cytokine release while preserving plaque-associated microglia (disease-associated microglia, DAM). Morphological and electrophysiological analyses demonstrated that CTX restored dendritic complexity, spine density, and hippocampal long-term potentiation (LTP), indicating improved synaptic integrity. Collectively, these findings identify CTX as a potent modulator of neuroimmune signaling that mitigates neuroinflammation and synaptic dysfunction in AD, suggesting its potential for repurposing as an immunomodulatory therapy for neurodegenerative diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117779"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163936","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":"Psychological stress and myocardial extracellular matrix remodeling- a pathologic synergy","authors":"Francis G. Spinale ,&nbsp;Brian R. Weil ,&nbsp;Umesh Sharma ,&nbsp;Susan Wood ,&nbsp;Fiona Hollis ,&nbsp;Giselle C. Meléndez ,&nbsp;Kristine Y. DeLeon-Pennell ,&nbsp;Amy D. Bradshaw ,&nbsp;Jennifer K. Lang ,&nbsp;John M. Canty ,&nbsp;Michael R. Zile","doi":"10.1016/j.bcp.2026.117795","DOIUrl":"10.1016/j.bcp.2026.117795","url":null,"abstract":"<div><div>Psychosocial stress has been identified to increase the development and severity of cardiovascular disease, particularly heart failure. An underlying structural factor for the development and progression of certain forms of heart failure is the accumulation of extracellular matrix-generically termed myocardial fibrosis. However, it remains unclear what pathways and mechanisms by which psychosocial stress intersects with the development of myocardial fibrosis. This review will focus upon animal models of psychosocial stress and specific signaling pathways which may be relevant to the development of myocardial fibrosis. This includes sympathetic efferent activation, localized inflammatory pathways, mitochondrial stress, and a key cell type responsible for myocardial fibrosis, the fibroblast. Finally, the functional and clinical implications on how myocardial fibrosis contributes to heart failure and exacerbated by psychosocial stress will be examined. The main take away from this session was to identify different animal models of psychosocial stress/PTSD and find common mechanisms of signaling and inflammation. A unifying postulate was that mitochondrial stress within the brain can cause activation of extrinsic (cytokines) and intrinsic (inflammasome) inflammatory pathways which result in the emergence of a profibrotic fibroblast and acceleration of myocardial fibrosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117795"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177706","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":"Targeting PDK4 attenuates neointimal hyperplasia and regulates VSMC phenotypic switching, apoptosis, and autophagy","authors":"Ankan Sarkar ,&nbsp;Sakeel Ahmed ,&nbsp;Monika Singh ,&nbsp;Zahid Bashir Zargar ,&nbsp;Sandip V Pawar ,&nbsp;Shyam Sunder Sharma ,&nbsp;Kanwaljit Chopra ,&nbsp;Manish Jain","doi":"10.1016/j.bcp.2026.117805","DOIUrl":"10.1016/j.bcp.2026.117805","url":null,"abstract":"<div><div>Neointimal hyperplasia, a predominant cause of restenosis and atherosclerosis, is regulated by the phenotypic modulation, migration and proliferation, of vascular smooth muscle cells (VSMCs). Pyruvate dehydrogenase kinase 4 (PDK4) has been identified as a key metabolic regulator linked to cancer cell proliferation. However, the specific mechanistic role of PDK4 in VSMC function and neointimal formation remains ambiguous. A combination of in-<em>silico</em> network pharmacology, in <em>vitro</em> primary murine VSMC assays, and in <em>vivo</em> mouse carotid artery wire injury models was used to study the role of PDK4. In-<em>silico</em> analysis revealed that the PDK4 inhibitor (PDK4-IN-1) modulates diverse biological processes, molecular functions, and KEGG pathways central to VSMC proliferation, apoptosis, differentiation, and vascular remodelling. Pharmacological inhibition of PDK4 using PDK4-IN-1 substantially suppressed proliferation and migration of PDGF-BB-stimulated VSMCs. PDK4 inhibition upregulated contractile markers (SM22α, α-SMA, SM-MHC), reduced transcript levels of <em>MMP2</em> and <em>MMP9</em>, and attenuated ERK and mTOR activation. It also increased cytosolic and mitochondrial ROS, lowered glutathione levels, and enhanced oxidative stress markers. Apoptosis was significantly upregulated, indicated by elevated Annexin V/PI, TUNEL positivity, <em>BAX/BAK</em> transcription and upregulation of caspase-3. Concurrently, autophagic flux was enhanced, with increased LC3, Beclin-1, and expression of <em>ATG7</em>, and <em>LAMP1</em>. In <em>vivo</em>, perivascular delivery of PDK4-IN-1 in the mouse carotid artery injury model significantly ameliorated neointimal hyperplasia. Inhibition of PDK4 perturbs pathological VSMC phenotypic switching, suppresses proliferation, promotes apoptosis and autophagy, and mitigates neointimal formation, highlighting PDK4 as a promising therapeutic target for vascular proliferative diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117805"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171754","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":"Corrigendum to “Comprehensive non-small cell lung cancer targets: From computational prediction to clinical breakthroughs in overcoming drug resistance” [Biochem. Pharmacol. 242(Part 2) (2025) 117333]","authors":"Wanjie Zheng ,&nbsp;Zhiheng He ,&nbsp;Jiarui Liu ,&nbsp;Yuting Zhang ,&nbsp;Chengjun Gong ,&nbsp;Baojie Wang ,&nbsp;Jie Shen ,&nbsp;Li Guo ,&nbsp;Tingming Liang","doi":"10.1016/j.bcp.2026.117778","DOIUrl":"10.1016/j.bcp.2026.117778","url":null,"abstract":"","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117778"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169929","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":"Momordin Ic suppresses breast cancer growth by targeting ACTL8‑dependent glutamine metabolism and PI3K/AKT/mTOR–MYC","authors":"Ao Guo ,&nbsp;Bijun Yang ,&nbsp;Aolin Xiao Huang ,&nbsp;Jie Ni ,&nbsp;Yanhui Zhang ,&nbsp;Qinlin Jiang ,&nbsp;Yunwen Yan ,&nbsp;Qichao Luo ,&nbsp;Jing Yang ,&nbsp;Bin Yuan","doi":"10.1016/j.bcp.2026.117761","DOIUrl":"10.1016/j.bcp.2026.117761","url":null,"abstract":"<div><div>Glutamine metabolism is a key driver of tumor progression, yet the molecular basis and prognostic relevance of glutamine metabolism–related genes in breast cancer (BC) remain incompletely defined. In this study, integrated analysis of public datasets identified Actin-like protein 8 (ACTL8) as a key prognostic gene significantly upregulated in BC tissue and associated with poor patient survival. In vitro, shRNA knockdown of ACTL8 reduced MYC expression and its downstream targets SLC1A5 and GLS1, suppressing cell proliferation, migration and invasion. This disruption led to impaired redox homeostasis as evidenced by reduced GSH/GSSG and NADPH/NADP⁺ ratios. Mechanistically, MYC overexpression restored metabolic enzymes and phenotypes but failed to rescue p-AKT levels, confirming ACTL8 acts upstream of the PI3K/AKT/mTOR axis. Virtual screening identified Momordin Ic as a small molecule that directly interacts with ACTL8. Surface plasmon resonance (SPR) and Thermal shift assay (TSA) confirmed this high-affinity binding, which destabilized ACTL8 and promoted its ubiquitin–proteasome degradation. Moreover, ACTL8 knockdown significantly attenuated the sensitivity of BC cells to Momordin Ic treatment, confirming ACTL8 as the specific therapeutic target. In vivo, suppression of ACTL8 markedly reduced tumor growth. Together, these findings establish ACTL8 as a key oncogenic driver of BC progression. Targeting ACTL8 offers a novel strategy to disrupt glutamine-dependent metabolic reprogramming, and Momordin Ic represents a promising lead agent to combat ACTL8-driven BC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117761"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099857","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":"The rare bile acid isoallolithocholic acid (IALCA) is an EphA2 antagonist sparing FXR and TGR5 receptors","authors":"Andrea Blesio ,&nbsp;Carmine Giorgio ,&nbsp;Francesca Romana Ferrari ,&nbsp;Stefano Sala ,&nbsp;Lisa Flammini ,&nbsp;Ilaria Zanotti ,&nbsp;Daniela Passeri ,&nbsp;Antimo Gioiello ,&nbsp;Lorenzo Sarcone ,&nbsp;Riccardo Castelli ,&nbsp;Kun Karnchanapandh ,&nbsp;Federica Vacondio ,&nbsp;Lorenzo Tagliazucchi ,&nbsp;Laura Scalvini ,&nbsp;Marco Mor ,&nbsp;Alessio Lodola ,&nbsp;Massimiliano Tognolini","doi":"10.1016/j.bcp.2026.117807","DOIUrl":"10.1016/j.bcp.2026.117807","url":null,"abstract":"<div><div>The role of the Eph/ephrin system is well recognized in various physiological and pathological processes, including acute inflammation and cancer. We previously discovered that the secondary bile acid lithocholic acid (LCA) is a competitive antagonist of Eph receptors. The utility of LCA as a pharmacological tool for investigating Eph/ephrin biology was hampered by its primary activity at the FXR and TGR5 receptors. A recent study of centenarians’ gut microbiomes revealed that a rare bile acid closely related to LCA, isoallolithocholic acid (IALCA), exerts marked protective effects on the intestinal epithelium, but its specific molecular target was unidentified. Considering the well-documented involvement of EphA2 in regulating intestinal epithelial/endothelial permeability, we asked whether IALCA could act through this receptor. Molecular docking and dynamics simulations predicted that IALCA binds within the ephrin-A1–binding pocket of EphA2. Our findings were validated through wet experiments, and IALCA emerged as a selective EphA2 inhibitor, blocking ephrin-A1 binding with low-micromolar potency. In functional studies, IALCA inhibited ephrin-A1–induced EphA2 phosphorylation, cell retraction, and rounding, confirming its antagonistic activity. Moreover, IALCA showed no detectable activity at the classical bile-acid receptors FXR, PXR, LXRα, or TGR5, thereby potentially linking its cellular and phenotypic effects to modulation of the Eph–ephrin system. As a final step, we demonstrated that IALCA also provides an attractive template for synthesizing new Eph antagonists. Overall, this work underscores the potential of the human gut microbiome as a reservoir of privileged chemical scaffolds for both fundamental pharmacology and therapeutic drug development.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117807"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199511","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":"Identification of a novel chalcone derivative as ferroptosis inducer through targeting TrxR in prostate cancer","authors":"Jun Yan ,&nbsp;Long Cheng ,&nbsp;Qing-qing Ma ,&nbsp;Qiao-xuan Zhang ,&nbsp;Shu Gan ,&nbsp;Hai-biao Lin ,&nbsp;Li-qiao Han ,&nbsp;Peng-wei Zhang ,&nbsp;Fen Ouyang ,&nbsp;Pei-feng Ke ,&nbsp;Xian-zhang Huang","doi":"10.1016/j.bcp.2026.117760","DOIUrl":"10.1016/j.bcp.2026.117760","url":null,"abstract":"<div><div>Prostate cancer (PCa) remains a major threat to male health. Due to the inevitable progression of incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT), it is an urgent need to seek out new therapeutic strategies that not dependent on androgen receptor (AR) signaling pathway. Through high-throughput screening of our in-house compound library, compound <strong>CD-15</strong>, a chalcone derivative, demonstrated remarkable anti-proliferative activity on AR-negative PCa cells at subnanomolar concentrations and completely blocked tumor growth in both cell line-derived xenograft (CDX) mice model and a zebrafish patient-derived xenograft (zPDX) model. Notably, <strong>CD-15</strong> displayed a more favorable safety profile than the clinically widely-used drug docetaxel. Leveraging drug affinity responsive target stability (DARTS) technology and virtual target screening, thioredoxin reductase (TrxR) was identified as the direct target of <strong>CD-15</strong>. Our study also found TrxR was over-expressed in the serum and tissues in PCa patients and TrxR1 knockdown partially attenuated the suppressive effect of <strong>CD-15</strong> in vitro and in vivo. Moreover, several means including BIAM assay, molecular docking, LC-MS/MS and DARTS analysis confirmed that <strong>CD-15</strong> covalently modified selenocysteine 498 (U) residues within the redox-active site of TrxR, leading to the enzyme inhibition. Mechanistically, <strong>CD-15</strong> exerted a dual anti-PCa mechanism, which was capable of inducing ferroptosis in a TrxR-dependent manner. Altogether, <strong>CD-15</strong> emerges as a promising candidate for the treatment of PCa and deserves further investigation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117760"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083552","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}