ACS Chemical Biology最新文献

Synthesis and Antimicrobial Specificities of Halogenated Tryptophan-Containing Nisin Variants. 含卤化色氨酸Nisin变体的合成及抗菌特性研究。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-09-12 DOI: 10.1021/acschembio.5c00632

Chenhui Wang, Sanne Tervoort, Oscar P Kuipers, Jaap Broos

{"title":"Synthesis and Antimicrobial Specificities of Halogenated Tryptophan-Containing Nisin Variants.","authors":"Chenhui Wang, Sanne Tervoort, Oscar P Kuipers, Jaap Broos","doi":"10.1021/acschembio.5c00632","DOIUrl":"https://doi.org/10.1021/acschembio.5c00632","url":null,"abstract":"Antimicrobial peptides, and in particular ribosomally produced and post-translationally modified peptides (RiPPs), are a potentially important class of candidate antibiotics for combating multidrug-resistant bacteria. Introduction of a halogenated Trp residue into a RiPP can possibly enhance antimicrobial efficacy and alter specificity, but this modification has hardly been explored. This study employs an efficient expression system utilizing a tryptophan auxotrophic Lactococcus lactis strain to biosynthetically and efficiently incorporate halogenated tryptophan analogues, namely 5-fluoro-tryptophan (5FW), 5-chloro-tryptophan (5CW), 5-bromo-tryptophan (5BW), as well as 5-methyl-tryptophan (5MW) at position 1 of I1W nisin A. Wild-type nisin and Trp-containing I1W nisin show a high and broad activity against four tested pathogens. However, the activity spectrum of the three different halogen atom containing nisin variants became more strain specific, as both increased and decreased activities were measured against the four tested pathogens. No trend between the chemical properties of the halogen atom (e.g., electronegativity, size) and the bioactivity of the nisin variants toward each of the four pathogens could be detected, suggesting strain specific antimicrobial activity mechanisms. These findings demonstrate that halogenated tryptophan analogues can be successfully incorporated into a bioactive RiPP produced by an auxotrophic L. lactis strain and underscore the utility of peptide halogenation for discovering novel antimicrobial agents with tailored pathogen specificity.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural Elucidation and Covalent Modulation of the Autorepressed Orphan Nuclear Receptor NR2F6. 自抑制孤儿核受体NR2F6的结构解析和共价调控。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-09-10 DOI: 10.1021/acschembio.5c00475

Guido J M Oerlemans, Maxime C M van den Oetelaar, Siebe P van den Elzen, Luc Brunsveld

{"title":"Structural Elucidation and Covalent Modulation of the Autorepressed Orphan Nuclear Receptor NR2F6.","authors":"Guido J M Oerlemans, Maxime C M van den Oetelaar, Siebe P van den Elzen, Luc Brunsveld","doi":"10.1021/acschembio.5c00475","DOIUrl":"https://doi.org/10.1021/acschembio.5c00475","url":null,"abstract":"The orphan nuclear receptor NR2F6 (Nuclear Receptor subfamily 2 group F member 6) is an emerging therapeutic target for cancer immunotherapy. Upregulation of NR2F6 expression in tumor cells has been linked to proliferation and metastasis, while in immune cells NR2F6 inhibits antitumor T-cell responses. Small molecule modulation of NR2F6 activity might therefore be a novel strategy in cancer treatment, benefiting from this dual role of NR2F6. However, there are no molecular strategies available for targeting NR2F6, hampered among others by lack of structural insights and appropriate biochemical assays. To overcome these challenges, several noncanonical nuclear receptor coregulator peptide motifs were identified to be constitutively recruited to the NR2F6 ligand binding domain (LBD). Co-crystallization of the NR2F6 LBD with a peptide from the coregulator Nuclear Receptor Binding SET Domain Protein 1 (NSD1) enabled, for the first time, the structural elucidation of the unliganded (apo) form of NR2F6. This revealed an autorepressed, homodimeric LBD conformation in which helix 12 folds over the canonical coregulator binding site, generating an alternative contact surface for NSD1 binding. Screening of a focused library of covalent NR probes identified compounds that preferentially target a cysteine residue near the NSD1 binding site, inhibiting NR2F6 coregulator recruitment. Combined, these results provide structural insights into the ligand-independent transcriptional activity of NR2F6 and may serve as a starting point for the development of novel NR2F6 modulators.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to "Identification and Characterization of the Biosynthesis of the Hybrid NRPS-NIS Siderophore Nocardichelin". 修正“nrpps - nis铁载体Nocardichelin的生物合成鉴定与表征”。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-09-02 DOI: 10.1021/acschembio.5c00636

Mercedes B Fisk, Jocelyn Barrera Ramirez, Collin E Merrick, Timothy A Wencewicz, Andrew M Gulick

引用次数: 0

Photoinduced Nitric Oxide Exchange in the Diazeniumdiolate Siderophore, Pandorachelin. 光诱导一氧化氮交换的双氮二酸铁载体。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-09-02 DOI: 10.1021/acschembio.5c00484

Melanie Susman, Christina Makris, Alison Butler

{"title":"Photoinduced Nitric Oxide Exchange in the Diazeniumdiolate Siderophore, Pandorachelin.","authors":"Melanie Susman, Christina Makris, Alison Butler","doi":"10.1021/acschembio.5c00484","DOIUrl":"https://doi.org/10.1021/acschembio.5c00484","url":null,"abstract":"C-diazeniumdiolate siderophores are a small class of photoactive bacterial Fe(III) chelators. Driven by genome mining, we discovered a new C-type diazeniumdiolate siderophore, pandorachelin, produced by the rhizospheric bacterium, Pandoraea norimbergensis DSM 11628. The biosynthetic gene cluster encoding the production of pandorachelin is conserved across several Pandoraea species. Pandoraea spp. are environmentally widespread and are increasingly prevalent clinical pathogens, spurring new interest in their metabolites. UV irradiation photolytically cleaves the N-N bonds within the diazeniumdiolate-containing graminine constituents of pandorachelin. With EPR spin trapping, we directly detect nitric oxide released from the two C-diazeniumdiolate ligands of pandorachelin upon UV irradiation. Additionally, we show that nitric oxide can react with the intermediates during the photoreaction to reconstruct the diazeniumdiolate groups via exchange of the distal nitric oxide (NO) and thereby recover Fe(III)-binding capacity. The photochemistry of this class of siderophores points to a broader biological role, both in their propensity to release the biological signaling molecule, nitric oxide, and in their ability to undergo photoinduced NO exchange.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Time-Resolved Analysis of Protein-Protein Ensembles Using a Destabilizing Domain to Map Dynamic Interactions of SARS-CoV-2 nsp15. 利用不稳定结构域对SARS-CoV-2 nsp15的动态相互作用进行蛋白质-蛋白质组合的时间分辨分析。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-09-01 DOI: 10.1021/acschembio.5c00377

Crissey Cameron, R Mason Clark, Adam M Metts, Runze M Jiang, Toya D Scaggs, Kwangho Kim, Gary A Sulikowski, Lars Plate

{"title":"Time-Resolved Analysis of Protein-Protein Ensembles Using a Destabilizing Domain to Map Dynamic Interactions of SARS-CoV-2 nsp15.","authors":"Crissey Cameron, R Mason Clark, Adam M Metts, Runze M Jiang, Toya D Scaggs, Kwangho Kim, Gary A Sulikowski, Lars Plate","doi":"10.1021/acschembio.5c00377","DOIUrl":"https://doi.org/10.1021/acschembio.5c00377","url":null,"abstract":"Dynamic protein-protein interactions are key drivers of many cellular processes. Determining the relative sequence and precise timing of these interactions is crucial for elucidating the functional dynamics of biological processes. Here, we developed a time-resolved analysis of protein-protein ensembles using a destabilizing domain (TRAPPED) to study protein-protein interactions in a temporal manner. We have taken advantage of a dihydrofolate reductase-destabilizing domain (DHFR(DD)) that can be fused to a protein of interest and is constitutively degraded by the proteosome. Addition of the ligand trimethoprim (TMP) can stabilize DHFR(DD), preventing proteasomal degradation of the fusion protein and thereby inducing accumulation in cells. We synthesized and optimized TRimethoprim Analog Probes that maintain stabilization activity and contain a terminal alkyne for Click functionalization and a thiol reactive group to covalently tag DHFR(DD). Click reaction with a biotin tag and subsequent streptavidin enrichment enable time-resolved mass spectrometric identification of interacting partners. We evaluated the timing of protein interactions of SARS-CoV-2 and SARS-CoV nonstructural protein 15 (nsp15) over a 2 h period. We found interactors GEMIN5 and YBX3, known regulators of SARS-CoV-2 infection that bind viral RNA, as well as CACYBP and FHL1 that implicate nsp15 in the disruption of host ERK1/2 signaling. We further revealed that these interactions remain relatively steady from 0 to 2 h post translation of nsp15. TRAPPED methodology can be applied to determine the sequence and timing of protein-protein interactions of temporally regulated biological processes such as viral infection or signal transduction.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chemoselective Installation of Electrophilic Warheads onto C-Terminal Peptide Hydrazides for Covalent Protease Inhibitor Synthesis. 共价蛋白酶抑制剂合成中c端肽酰肼上亲电战斗部的化学选择性安装。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-27 DOI: 10.1021/acschembio.5c00281

Shaun O'Hare, Kateryna A Tolmachova, Jeffrey W Bode

{"title":"Chemoselective Installation of Electrophilic Warheads onto C-Terminal Peptide Hydrazides for Covalent Protease Inhibitor Synthesis.","authors":"Shaun O'Hare, Kateryna A Tolmachova, Jeffrey W Bode","doi":"10.1021/acschembio.5c00281","DOIUrl":"https://doi.org/10.1021/acschembio.5c00281","url":null,"abstract":"Covalent binders to protein targets offer a powerful approach to the generation of tool compounds and an increasingly common strategy for therapeutic development. The installation of electrophiles onto peptide binders, however, is often precluded by standard conditions for peptide synthesis, which involve strong nucleophiles, bases, and acids. The introduction of C-terminal electrophiles is further complicated by the C → N directionality of standard solid-phase peptide synthesis. Here, we employ chemoselective, site-specific functionalization of C-terminal peptide acyl hydrazides to install strong electrophiles on unprotected peptides. Using automated, high-throughput liquid handling and solid-phase extraction techniques, we have established a combinatorial workflow for the synthesis of peptide-derived covalent protease inhibitors. This methodology enables the synthesis and initial screening of inhibitor libraries in a 96-well plate format without the need for chromatographic purification prior to enzyme inhibition studies, leading to the identification of covalent Cathepsin S inhibitors active in the nanomolar range. When tested in cells, the covalent probes revealed strong off-target interactions with the protein disulfide isomerase PDIA1. These findings both underscore the role of chemoselective chemistries for covalent probe synthesis and highlight the utility of the platform for both the rapid identification of potent inhibitors and the detection of potential off-target interactions.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Small-Molecule Covalent Stabilization and Inhibition of the TEAD·YAP1 Transcription Factor in Cancer Cells. 肿瘤细胞中TEAD·YAP1转录因子的小分子共价稳定和抑制

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-27 DOI: 10.1021/acschembio.5c00283

I-Ju Yeh, Khuchtumur Bum-Erdene, Mona K Ghozayel, Giovanni Gonzalez-Gutierrez, Samy O Meroueh

{"title":"Small-Molecule Covalent Stabilization and Inhibition of the TEAD·YAP1 Transcription Factor in Cancer Cells.","authors":"I-Ju Yeh, Khuchtumur Bum-Erdene, Mona K Ghozayel, Giovanni Gonzalez-Gutierrez, Samy O Meroueh","doi":"10.1021/acschembio.5c00283","DOIUrl":"https://doi.org/10.1021/acschembio.5c00283","url":null,"abstract":"Transcriptional enhanced associate domain transcription factors (TEAD1 to TEAD4) bind to transcriptional coactivator Yes-Associated Protein (YAP1) or its paralog transcriptional coactivator with PDZ-binding motif (TAZ) to regulate Hippo pathway target genes. The Hippo pathway is a conserved signaling pathway that regulates organ size and cell fate by controlling cell proliferation and apoptosis. Here we report small acrylamide molecules that form a covalent bond with a conserved cysteine at the TEAD palmitate pocket. Binding studies showed profound stabilization of TEADs by the small molecules, and cocrystal structures reveal that the compounds mimic the binding mode of palmitate. The small molecules achieved submicromolar binding constants and subhour reaction half-lives for all four TEADs. In mammalian cells, the compounds stabilize the TEAD•YAP1 interaction yet inhibit the TEAD transcription factor activity. Unexpectedly, several compounds degraded TEAD and YAP1 proteins and inhibited cancer cell viability. This work suggests that degradation of TEAD and YAP1 may amplify the antitumor effects of small molecules targeting the TEAD palmitate pocket, with implications for other cancer targets featuring allosteric lipid-binding sites.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design of Hyperglycosylated Zika Virus E Proteins that Focus Antibody Recognition on the Complex E Dimer Epitope. 将抗体识别集中在复合物E二聚体表位上的高糖基化寨卡病毒E蛋白的设计

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-23 DOI: 10.1021/acschembio.5c00253

Margarette C Mariano, Matthew Gregory Hvasta, Kimberly A Dowd, Wei-Chiao Huang, Helen S Jung, Lamount R Evanson, George I Georgiev, Julia C Frei, Jonathan F Lovell, Theodore C Pierson, Brian Kuhlman, Jonathan R Lai

{"title":"Design of Hyperglycosylated Zika Virus E Proteins that Focus Antibody Recognition on the Complex E Dimer Epitope.","authors":"Margarette C Mariano, Matthew Gregory Hvasta, Kimberly A Dowd, Wei-Chiao Huang, Helen S Jung, Lamount R Evanson, George I Georgiev, Julia C Frei, Jonathan F Lovell, Theodore C Pierson, Brian Kuhlman, Jonathan R Lai","doi":"10.1021/acschembio.5c00253","DOIUrl":"https://doi.org/10.1021/acschembio.5c00253","url":null,"abstract":"Zika virus (ZIKV) and dengue virus serotypes 1-4 (DENV1-4) are flaviviruses spread by Aedes mosquitoes. ZIKV infection can cause Guillain-Barré syndrome and microcephaly, while severe dengue can lead to hemorrhagic fever and death. DENV infection of ZIKV-immune individuals is linked to severe clinical outcomes due to antibody-dependent enhancement (ADE) of infection. Thus, the development of broadly protective vaccines is an important objective. We focus on the E dimer epitope (EDE) of ZIKV, which is targeted by broadly neutralizing antibodies that protect against ZIKV and DENV1-4. We engineered ZIKV E dimer variants containing non-native asparagine-linked glycosylation sites to block antibody responses to regions outside the EDE using a structure-based iterative design approach. One candidate, SC30m53, bound EDE mAbs but not other mAbs and induced a potently neutralizing response against ZIKV and moderately cross-neutralizing responses against DENV1-3 in mice. These findings suggest that hyperglycosylation provides a promising approach to focusing the immune response on key epitopes.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Conformational Frustration at the Protein-Glycan Interface of a Nonmitogenic Anti-HIV Lectin Results in Altered Quaternary Structure. 一种非有丝分裂性抗hiv凝集素在蛋白-聚糖界面的构象受挫导致了四元结构的改变。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-22 DOI: 10.1021/acschembio.5c00347

Vaishali Narayanan, Avadhesha Surolia, Ashok Sekhar

{"title":"Conformational Frustration at the Protein-Glycan Interface of a Nonmitogenic Anti-HIV Lectin Results in Altered Quaternary Structure.","authors":"Vaishali Narayanan, Avadhesha Surolia, Ashok Sekhar","doi":"10.1021/acschembio.5c00347","DOIUrl":"https://doi.org/10.1021/acschembio.5c00347","url":null,"abstract":"Lectins are carbohydrate-binding proteins that have enormous therapeutic value because of their potent antiviral activity. However, the design of lectins for targeted intervention is marred by our poor understanding of protein-glycan recognition. Here, we focus on the mannose-specific lectin horcolin, which is nonmitogenic and shows dose-dependent inhibition of HIV infection. Saturation transfer and relaxation dispersion NMR experiments reveal that the lectin-glycan interface is conformationally frustrated, resulting in the formation of a minor state with a millisecond time-scale lifetime. There is a rearrangement of the quaternary structure of horcolin in this minor state that manifests as a noncanonical tetramer. The glycan-binding site is sequestered at the tetrameric interface, suggesting that the tetramer could serve as an autoinhibitory conformation. However, glycan recognition itself occurs via the major dimeric conformation through a \"ground-state conformational selection\" mechanism. We also demonstrate that the tetramer is destabilized by mannose and that conformational frustration is alleviated in the lectin-glycan complex. Our work illustrates how the architecture of biomolecular assemblies is molded in response to conflicting evolutionary signals such as folding and recognition. The work also provides insights into protein-glycan recognition that could have potential implications for deploying lectins as antiviral agents.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dovitinib Ameliorates Inflammation-Related Diseases by Inhibiting Necroptosis and Ferroptosis. 多维替尼通过抑制坏死性下垂和铁下垂改善炎症相关疾病。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-21 DOI: 10.1021/acschembio.5c00327

Yingying Lin, Jianting Feng, Mingyuan Zhao, Libo Zhang, Yan Li, Xuan Chen, Chuibing Lin, Junxiong Lin, Qiaofa Lin, Jingyi Li, Lanqin Wu, Lisheng Li

{"title":"Dovitinib Ameliorates Inflammation-Related Diseases by Inhibiting Necroptosis and Ferroptosis.","authors":"Yingying Lin, Jianting Feng, Mingyuan Zhao, Libo Zhang, Yan Li, Xuan Chen, Chuibing Lin, Junxiong Lin, Qiaofa Lin, Jingyi Li, Lanqin Wu, Lisheng Li","doi":"10.1021/acschembio.5c00327","DOIUrl":"https://doi.org/10.1021/acschembio.5c00327","url":null,"abstract":"Abnormal and dysregulated cell death plays important roles in organ injury. Necroptosis and ferroptosis are two distinct types of regulated cell death that can trigger inflammation and are involved in organ injury. The inhibition of necroptosis and ferroptosis is proposed to be beneficial for treating multiple pathological conditions. To find out necroptosis and ferroptosis inhibitors, we used a small-molecule compound library for screening and identified a clinically advanced compound, Dovitinib (Dov), as a potent dual inhibitor of necroptosis and ferroptosis. Dov inhibited tumor necrosis factor (TNF)-induced necroptosis by regulating receptor-interacting protein kinase 1 (RIPK1) and alleviated TNF-mediated systemic inflammatory response syndrome. Additionally, Dov inhibited ferroptosis by regulating the NRF2/HMOX1 axis and lipid peroxidation and protected against concanavalin A-induced acute liver injury. Thus, our work revealed that Dov is a dual inhibitor of necroptosis and ferroptosis and provides a potential therapeutic drug or combination approach for treating necroptosis- and ferroptosis-related diseases.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0