Journal of Biological Chemistry最新文献

{"title":"The Stage-Specific Roles of HIF-1α in Regulating mESCs Pluripotency During Oxygen Transition.","authors":"Meng Li, Yang Cao, Huaizhang Jin, Ao Wang, Jian Ruan, Shan Lu, Guosheng Lv, Guoping Zhu, Yang Lei, Xiaopeng Shen","doi":"10.1016/j.jbc.2025.110344","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110344","url":null,"abstract":"<p><p>Hypoxia-inducible factor 1-alpha (HIF-1α) is a key transcription factor in cellular responses to oxygen levels. This study investigated HIF-1α's binding dynamics to the genome during the transition from normoxia to hypoxia in mouse embryonic stem cells (mESCs). Analyzing HIF-1α ChIP-seq data under normoxia, acute hypoxia, and stable hypoxia revealed a \"bind-release-bind\" pattern, with the weakest binding during acute hypoxia and the strongest during stable hypoxia. Gene ontology (GO) and KEGG analyses identified distinct gene sets and pathways regulated by HIF-1α in these conditions, with significant effects on pluripotency under normoxia and stable hypoxia. HIF-1α also partnered with different transcription factors depending on the oxygen level, further influencing its functions. RNA-seq data and knockdown experiments confirmed HIF-1α's essential role in maintaining mESCs pluripotency under normoxia and stable hypoxia, with minimal impact under acute hypoxia. These findings enhance our understanding of HIF-1α's regulatory mechanisms and its role in cellular hypoxic responses.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110344"},"PeriodicalIF":4.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248064","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}

{"title":"The phosphatase activity of the PPP2R5D-PP2A holoenzyme modulates liprin-α1 liquid-liquid phase separation.","authors":"Abigail Mayer, Rita Derua, Elijah Spahn, Iris Verbinnen, Yang Zhang, Michelle Guzman, Mark R Swingle, Brian E Wadzinski, Richard Honkanen, Veerle Janssens, Houhui Xia","doi":"10.1016/j.jbc.2025.110349","DOIUrl":"10.1016/j.jbc.2025.110349","url":null,"abstract":"<p><p>Liprin-α1 is a widely expressed scaffolding protein known to regulate cellular processes such as cell motility and synaptic transmission through assembly of localized higher-order molecular complexes. However, the dynamic regulation of these complexes remains poorly understood. Liquid-liquid phase separation (LLPS) is a process that concentrates proteins into cellular nanodomains, facilitating efficient spatiotemporal signaling. Whether liprin-α1 undergoes regulated LLPS remains unclear. MS-based interactomics identified PPP2R5D, the regulatory B56δ subunit of PP2A, as a liprin-α1 interaction partner via a canonical short linear motif (SLiM) in its N-terminal dimerization domain. Mutation of SLiM4 nearly abolished liprin-α1 interaction with PP2A holoenzyme and resulted in a significant increase in GFP-liprin-α1 LLPS in HEK293 cells. Consistently, GFP-liprin-α1 exhibited increased droplet formation in PPP2R5D knockout HEK293 cells. Phospho-analysis of liprin-α1 SLiM4 mutant via MS revealed increased phosphorylation of multiple Ser/Thr sites, including S763, as validated by a novel phospho-specific antibody. A liprin-α1 S763E phospho-mimetic mutant appeared sufficient to drive LLPS. Expression of the PPP2R5D missense variant E420K, recurrently found in Houge-Janssens Syndrome Type 1 compromised suppression of liprin-α1 LLPS, correlating with increased liprin-α1 S763 phosphorylation. Mechanistically, a liprin-α1 E942A mutant unable to bind liprin-β1 underwent increased LLPS, despite preserved PPP2R5D holoenzyme binding. Furthermore, liprin-α1/β1 heterodimerization significantly decreased under conditions where liprin-α1 LLPS was promoted, i.e. upon SLiM4 or S763E mutation in wild type cells, or in PPP2R5D knockout and PPP2R5D E420K knock-in cells. Our findings identify liprin-β1 and PPP2R5D-PP2A as potent inhibitors of liprin-α1 LLPS, with PP2A contributing to liprin-α1/β1 heterodimerization via phosphorylation of at least liprin-α1 S763.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110349"},"PeriodicalIF":4.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248063","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}

{"title":"Molecular mechanism of antagonists recognition and regulation of the α_1A- adrenoceptor. (α_1A-Adrenoceptor Antagonist Recognition).","authors":"Sisi Liu, Haizhan Jiao, Yuyong Tao, Dandan Wang, Qiong Guo","doi":"10.1016/j.jbc.2025.110348","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110348","url":null,"abstract":"<p><p>The α₁-adrenoceptor (α₁AR) is a critically important class of G protein-coupled receptors (GPCRs), comprising three subtypes: α_1AAR, α_1BAR, and α_1DAR. Currently, drugs targeting α₁AR have been used in the treatment of various diseases. Notably, antagonists of α₁AR play a pivotal role in the management of benign prostatic hyperplasia (BPH). In recent years, researchers have developed selective antagonists for the α_1AAR subtype that have a minimal impact on blood pressure for the treatment of BPH. However, these agents still exhibit certain side effects, necessitating the continuous development of new medications to mitigate adverse reactions while achieving more precise regulation. We report the cryo-EM structures of the α₁AR selective antagonist doxazosin and the α_1AAR subtype selective antagonist silodosin in complex with α_1AAR, demonstrating that M292^6.55 and V185^5.39 are key residues that confer subtype selectivity to silodosin. Additionally, modifications to α_1BAR enhanced silodosin's inhibitory efficacy against α_1BAR. These findings deepen our understanding of the recognition patterns of α_1AAR antagonists, revealing the molecular principles underlying the selective binding of silodosin to α_1AAR and promoting further research and development of subtype selective drugs targeting α_1AAR.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110348"},"PeriodicalIF":4.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248060","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}

{"title":"A glycine at position 105 leads to clavulanic acid and avibactam resistance in class A β-lactamases.","authors":"Marko Radojković, Aleksandra Chikunova, Saar F Koene, Monika Timmer, Sivanandam V Natarajan, Aimee L Boyle, Marcellus Ubbink","doi":"10.1016/j.jbc.2025.110347","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110347","url":null,"abstract":"<p><p>β-Lactamase enzymes exhibit extraordinary adaptive potential, thus rendering many β-lactam drugs ineffective. The residue at Ambler position 105, also known as the gatekeeper residue, plays an important role in substrate recognition, but its implication in inhibition mechanisms is understudied and obscure. To inspect the relationship between inhibitor-resistant phenotypes and residues at this position, we performed site-saturation mutagenesis and extensive fitness profiling of five distinct class A β-lactamases using deep sequencing. We found that inhibitor resistance is readily detectable, with variants harboring Gly or Arg being the least susceptible to inhibitors. Mutation of Ile105 to Arg in the β-lactamase BlaC simultaneously enhances activity for carbenicillin and the ability to evade clavulanic acid inhibition. The Y105G substitution in two clinically important enzymes, CTX-M-14 and TEM-1, confers greatly reduced in vitro sensitivity to avibactam, which we attribute to elevated conformational flexibility of the inhibitor within the active site. The findings presented in this study underpin the gatekeeper residue as a possible mutational hotspot and might aid the design of novel β-lactamase inhibitors.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110347"},"PeriodicalIF":4.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247983","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}

{"title":"Dimerization of the BAR domain-containing protein FAM92A modulates lipid binding and interaction with CBY1.","authors":"Xiaohan Xu, Jing Ren, Jianchao Li","doi":"10.1016/j.jbc.2025.110346","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110346","url":null,"abstract":"<p><p>BAR (Bin/Amphiphysin/Rvs) domain proteins drive membrane remodeling critical for cellular processes like ciliogenesis and organelle morphology. FAM92A (family with sequence similarity 92A), a classical BAR protein, regulates ciliary assembly, mitochondrial ultrastructure, and neuronal membrane dynamics, yet its molecular mechanisms remain elusive. Here, we determined the 2.2 Å crystal structure of the mouse FAM92A BAR domain, revealing an antiparallel, crescent-shaped homodimer. Structure-guided mutagenesis revealed that positively charged clusters on the concave surface are critical for lipid binding and identified residues essential for dimerization. We further demonstrated that FAM92A BAR directly binds the N-terminal region of Chibby1 (CBY1), a ciliary protein, with their respective dimerizations synergistically enhancing affinity. These findings elucidate the structural basis of FAM92A's membrane remodeling and CBY1 interaction, providing a molecular framework for its function in ciliogenesis and suggesting broader implications for FAM92 family proteins.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110346"},"PeriodicalIF":4.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247985","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}

{"title":"Molecular consequences of SCA5 mutations in the spectrin-repeat domains of β-III-spectrin.","authors":"Sarah A Denha, Naomi R DeLaet, Abeer W Abukamil, Angelica N Alexopoulos, Amanda R Keller, Matthew T Thiel, Alexandra E Atang, Adam W Avery","doi":"10.1016/j.jbc.2025.110350","DOIUrl":"10.1016/j.jbc.2025.110350","url":null,"abstract":"<p><p>Spinocerebellar ataxia type 5 (SCA5) mutations in the protein β-III-spectrin cluster to the N-terminal actin-binding domain (ABD) and the central spectrin-repeat domains (SRDs). We previously reported that a common molecular consequence of ABD-localized SCA5 mutations is increased actin binding. However, little is known about the molecular consequences of the SRD-localized mutations. It is known that the SRDs of β-spectrin proteins interact with α-spectrin to form an α/β-spectrin dimer. In addition, it is known that SRDs neighbouring the β-spectrin ABD enhance actin binding. Here, we tested the impact of the SRD-localized R480W and E532_M544del mutations on the binding of β-III-spectrin to α-II-spectrin and actin. R480W is associated with a severe infantile onset form of SCA5, while E532_M544del is associated with milder symptoms that begin in adulthood. We show that both the R480W and E532_M544del mutants can bind α-II-spectrin. However, E532_M544del causes partial uncoupling of complementary SRDs in the α/β-spectrin dimer. Further, the R480W mutant forms large intracellular inclusions when co-expressed with α-II-spectrin in cells, supporting that R480W grossly disrupts the α-II/β-III-spectrin complex. Moreover, actin-binding assays show that E532_M544del, but not R480W, increases β-III-spectrin actin binding. Additionally, we demonstrate that R480W α-II/β-III-spectrin inclusions contain F-actin, accumulate the spectrin-binding protein ankyrin-R, and localize immediately adjacent to the Golgi complex. Two additional infantile onset mutations, R437W and R437Q, but not the adult onset T472M mutation, also cause formation of large α-II/β-III-spectrin inclusions. We suggest that the intracellular inclusions caused by R480W, R437W and R437Q drive the more severe disease symptoms associated with these mutations.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110350"},"PeriodicalIF":4.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248059","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}

{"title":"Identification and characterization of mono- and bifunctional galactan synthases in the pediatric pathogen Kingella kingae.","authors":"Eric A Porsch, Mikel Jason Allas, Nina R Montoya, Vanessa L Muñoz, Li Tan, Artur Muszyński, Parastoo Azadi, Stephen N Hyland, Catherine L Grimes, Tzu-Ting Kao, Todd L Lowary, Joseph W St Geme","doi":"10.1016/j.jbc.2025.110345","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110345","url":null,"abstract":"<p><p>The emerging pediatric pathogen Kingella kingae elaborates a lipopolysaccharide (LPS) that is extended with a galactofuranose homopolymer called galactan, which is a key virulence determinant that contributes to resistance to complement-mediated and neutrophil-mediated killing. Previous work has demonstrated that the pamABCDE locus is required for galactan synthesis. In this study, mutational studies suggested that the pamC gene product is a UDP-galactofuranose (Galf) transferase and is the galactan synthase. Analysis of genome sequence data revealed two distinct pamC alleles designated pamC1 and pamC2, which correlate with the two galactan structures in K. kingae. Examination of isogenic mutants expressing either pamC1 or pamC2 demonstrated that the pamC alleles are the determinants of galactan structure. Experiments with recombinant PamC1 and PamC2 in vitro established that these proteins are galactan synthases capable of extending synthetic Galf disaccharide acceptors in the presence of UDP-Galf. Homology analysis identified critical amino acids that are essential for PamC1 and PamC2 enzymatic activity both in vitro and in K. kingae. Structural analysis of the in vitro-modified synthetic acceptors implicated PamC1 as a monofunctional enzyme capable of generating a β-(1→5) Galf linkage and PamC2 as a bifunctional enzyme capable of generating β-(1→3) and β-(1→6) Galf linkages. This study advances our understanding of the GT2 family of UDP-galactofuranosyltransferases.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110345"},"PeriodicalIF":4.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248056","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}

{"title":"A versatile fluorescence polarization based deubiquitination assay using an isopeptide bond substrate mimetic (IsoMim).","authors":"Jiatong Zhang, Jed Allen, Stephanie J Ward, Lodewijk V Dekker, Ingrid Dreveny","doi":"10.1016/j.jbc.2025.110342","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110342","url":null,"abstract":"<p><p>Deubiquitinases (DUBs) play a critical role in the regulation of various cellular processes, such as protein homeostasis and signaling, rendering them attractive drug targets. However, the generation of reagents for measuring DUB activity typically involves several steps and is not straight forward. Here, we report the development and characterization of a novel fluorescent polarization assay using an isopeptide bond substrate mimetic (IsoMim) that can be made recombinantly in high yields. The IsoMim assay was able to discern the differential activity of ubiquitin specific protease family members (USP4, USP15, USP11 and USP2), the ubiquitin C-terminal hydrolase UCHL3 and the Machado-Joseph Domain deubiquitinase JOSD2. A competition assay format of the assay was developed that discerned differences between the close paralogues USP15, USP4 and USP11 in interacting with mono-ubiquitin, the isopeptide mimetic ubiquitin-GGG and the C-terminal truncation variant ubiquitin (1-74). Moreover, dose-response curves and associated pIC50 values using the broad-spectrum inhibitor PR-619 confirmed differential inhibition in the low μM range for four tested DUBs. The successful discrimination of DUB activity and inhibition, and the easily scalable generation of the substrate make the IsoMim assay method applicable for high-throughput screening (HTS). This was ascertained in a 'pseudo HTS screen' for USP4 inhibitors in which PR-619 was successfully identified as a 'pseudo hit'. The developed assay provides a valuable tool for probing DUB activity and the identification and characterization of DUB inhibitors and has the potential to accelerate drug discovery efforts in this area.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110342"},"PeriodicalIF":4.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247984","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}

{"title":"FHL2 Facilitates LUSC Growth and Therapy Resistance through PI3K/AKT/mTOR Activation.","authors":"Lingxian Zhang, Dingguo Wang, Lei Zeng, Shiwei Chen, Kunchao Li, Tiankai Yuan, Jing Wang, Xiong Ma, Shuqiang Zhu, Yongbing Wu","doi":"10.1016/j.jbc.2025.110332","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110332","url":null,"abstract":"<p><p>Four and a half LIM domains protein 2 (FHL2) acts as a crucial role in tumorigenesis and progression. This study explored its involvement in lung squamous cell carcinoma (LUSC). Bioinformatics analysis assessed FHL2 expression and survival outcomes in non-small cell lung cancer (NSCLC). Subsequently, immunohistochemistry (IHC), qPCR, and Western blotting (WB) were performed to assess FHL2 levels in LUSC tissue microarrays (TMA) and cell lines. In vitro, CCK-8, plate colony formation, wound healing, and Matrigel Transwell assays were conducted to investigate the effects of FHL2 on LUSC cell proliferation, migration, and invasion. In vivo, xenograft tumor models were utilized to evaluate the role of FHL2 in LUSC progression. Mechanistically, immunoprecipitation (IP) and proximity ligation assays (PLA) were performed to explore the interaction between FHL2 and c-Jun. The cycloheximide (CHX) chase assay was conducted to assess c-Jun stability in the context of FHL2 overexpression or knockdown. The influence of differential FHL2 expression on the PI3K/AKT/mTOR (PAM) signaling pathway was analyzed via WB. Furthermore, xenograft tumor models, WB, and IHC were employed to determine whether FHL2 mediates LUSC resistance to afatinib. FHL2 expression was significantly upregulated in LUSC tissues, as demonstrated by the TCGA database analysis and validated through IHC staining of TMA. Moreover, elevated FHL2 expression was correlated with poor prognosis in LUSC patients. FHL2 overexpression enhanced LUSC cell proliferation, migration, and invasion in vitro while accelerating xenograft tumor growth in vivo. In contrast, FHL2 knockdown exhibited the opposite effects. Mechanistically, FHL2 interacts with c-Jun and suppresses its ubiquitination, thereby stabilizing the c-Jun protein, upregulating PDK1 expression, and subsequently activating the PAM signaling pathway. Notably, FHL2 overexpression induced afatinib resistance in LUSC cells, and patients with afatinib resistance exhibited high levels of FHL2 expression. Our results demonstrate that FHL2 promotes LUSC progression and induces afatinib resistance by regulating the PAM signaling pathway. FHL2 may serve as a crucial prognostic marker for the survival outcomes of LUSC patients and a promising therapeutic target for their treatment.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110332"},"PeriodicalIF":4.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247987","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}

{"title":"The gut microbiota mediates epoxy eicosanoid metabolism in the colon.","authors":"Nan Jing, Matthew L Edin, Yige Wang, Jun Yang, Fred B Lih, Vladimir Yeliseyev, Fuhang Liu, Yimei Ding, Darryl C Zeldin, Guodong Zhang","doi":"10.1016/j.jbc.2025.110338","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110338","url":null,"abstract":"<p><p>The metabolism of polyunsaturated fatty acids by cytochrome P450 (CYP) monooxygenases generates fatty acid epoxides, which are endogenous lipid mediators with potent actions to regulate inflammation, immune responses, vascular tone, and other critical biological processes. While previous research about their biosynthesis has focused on host metabolic enzymes, the role of gut microbiota remains largely unknown. Here, we demonstrate that the gut microbiota directly participates in the metabolism of fatty acid epoxides in the colon by catalyzing their conversion to fatty acid diols, thereby modulating colonic concentrations of these lipid mediators and associated biological actions. Using LC-MS/MS to analyze CYP-derived eicosanoids in the colons of conventionally raised versus germ-free or antibiotic-treated mice, we find that gut microbiota decreases colonic levels of fatty acid epoxides. Mechanistically, we find that the gut microbiota-mediated changes in colonic CYP eicosanoids are not driven by altered host biosynthetic enzyme expression; instead, gut microbes directly catalyze the hydrolysis of fatty acid epoxides to diols. Given the critical roles of CYP eicosanoids in regulating human health, our findings suggest that microbial metabolism of these lipid mediators may contribute to the mechanism by which gut microbiota influences host metabolism and disease development.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110338"},"PeriodicalIF":4.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248062","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}