Molecular Pharmacology最新文献

{"title":"Differential RELA and GR recruitment to the BIRC3/BIRC2 locus: Molecular insight as to combinatorial regulation by proinflammatory cytokines and glucocorticoid.","authors":"Andrew J Thorne, Alex Gao, Amandah Necker-Brown, Akanksha Bansal, Keerthana Kalyanaraman, Priyanka Chandramohan, Sarah K Sasse, Anthony N Gerber, Mahmoud M Mostafa, Robert Newton","doi":"10.1016/j.molpha.2025.100073","DOIUrl":"10.1016/j.molpha.2025.100073","url":null,"abstract":"<p><p>In pulmonary epithelial cells, baculoviral inhibitor of apoptosis repeat-containing (BIRC) gene, BIRC3, and to a lesser extent, BIRC2, mRNAs were upregulated by interleukin (IL)-1β and tumor necrosis factor-α. Glucocorticoids also induced BIRC3 mRNA and the glucocorticoid receptor (GR) was recruited to GR-binding regions (GBRs) proximal to, and within, BIRC3 in A549 and BEAS-2B cells. Four such GBRs drove glucocorticoid-inducible, Organon 34517-antagonized, transcription in A549 cells. IL-1β and tumor necrosis factor-α recruited the nuclear factor (NF)-κB transactivating subunit, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), to RELA-binding regions (RBRs) (R4 and R7) upstream of the BIRC3 and BIRC2 transcription start sites. These RBRs drove IL-1β-inducible transcription that involved NF-κB. Thus, direct regulation of BIRC3 by GR and BIRC3/BIRC2 by NF-κB is indicated. IL-1β-plus-budesonide also recruited RELA to multiple GBRs, whereas GR was recruited to the main IL-1β-induced RBR (R4), effects that correlated with positive IL-1β/glucocorticoid transcriptional cooperativity or additivity. At the R5 GBR, RELA was not recruited and both GR binding and glucocorticoid-dependent transcription reduced (infra-additivity) on cotreatment. Similarly, the R7 RBR barely recruited GR and IL-1β-induced transcription showed infra-additivity with IL-1β-plus-glucocorticoid. R8 recruited GR and RELA primarily with IL-1β-plus-glucocorticoid and revealed transcriptional synergy. Thus, GR/RELA-corecruitment yielded positive cooperative and additive transcriptional effects, whereas recruiting one factor alone associated with infra-additivity. Furthermore, DNA looping revealed how multiple RBRs/GBRs may integrate to control transcription. Because IL-1β- and glucocorticoid-dependent coupregulation of apoptotic/antiapoptotic genes was widespread, the combinatorial recruitment of RELA/GR to regulatory genes, including BIRC3, CFLAR plus others in the NF-κB pathway, may be critical to cell fate determination in inflammation. SIGNIFICANCE STATEMENT: Identification of functional GR- and RELA-binding regions at the BIRC3/BIRC2 locus explains the upregulation of BIRC3 expression by glucocorticoids and inflammatory cytokines. Cytokine-plus-glucocorticoid cotreatment revealed positive cooperative and additive interactions between GR and RELA, whereas DNA regions binding only one factor showed reduced effects on binding and transcription. These region-specific outcomes, combined with DNA looping between regulatory regions, provides insight as to how factors at multiple DNA regions may integrate their outputs to produce combinatorial regulation of apoptotic/antiapoptotic genes.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 10","pages":"100073"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Investigation of the binding mode of clobenprobit at CXCR4 and development of novel anti-inflammatory compounds with enhanced activity and minimal antagonist effects\" [Molecular Pharmacology 107 (2025) 100055].","authors":"Birgit Caspar, Nassima Bekaddour, Séverine Grinberg, Dominique Cathelin, Ivana Stoilova, Stephane Giorgiutti, Vincent Gies, Anne-Sophie Korganow, Nicolas Pietrancosta, Didier Roche, Vincent Rodeschini, Jean-Philippe Herbeuval","doi":"10.1016/j.molpha.2025.100071","DOIUrl":"10.1016/j.molpha.2025.100071","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 10","pages":"100071"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to \"17β-Estradiol, Genistein, and 4-Hydroxytamoxifen Induce the Proliferation of Thyroid Cancer Cells through the G Protein-Coupled Receptor GPR30\" [Mol Pharmacol 70 (2006) 1414-1423].","authors":"Adele Vivacqua, Daniela Bonofiglio, Lidia Albanito, Antonio Madeo, Vittoria Rago, Amalia Carpino, Anna Maria Musti, Didier Picard, Sebastiano Andò, Marcello Maggiolini","doi":"10.1016/j.molpha.2025.100082","DOIUrl":"10.1016/j.molpha.2025.100082","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 10","pages":"100082"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol residence time drives regulation of the G protein-coupled cholecystokinin receptor.","authors":"Chirine Toufaily, Yuanyuan Ma, Emmanuel D Barbosa, Kaleeckal G Harikumar, Denise Wootten, Patrick M Sexton, Wei Liu, Laurence J Miller","doi":"10.1016/j.molpha.2025.100074","DOIUrl":"10.1016/j.molpha.2025.100074","url":null,"abstract":"<p><p>Membrane cholesterol modulates the ability of cholecystokinin to act at the type 1 cholecystokinin receptor (CCK1R), with elevated levels of this lipid that can be present in obesity, disrupting stimulus-activity coupling. This occurs via direct effect on a cholesterol association (cholesterol recognition/interaction amino acid consensus) motif within CCK1R, whereas an analogous motif is present in the type 2 cholecystokinin receptor (CCK2R) with no functional impact of cholesterol on that receptor. We recently demonstrated that surface residues surrounding this motif in these 2 G protein-coupled receptors could be exchanged as a group to convert their cholesterol sensitivity. We now evaluate each of these residues individually and use molecular dynamics to study cholesterol interactions with this site. These studies show that cholesterol occupies this motif in both CCK1R and CCK2R with similar dominant poses in both receptors in normal, as well as in elevated cholesterol environments. The dominant pose of cholesterol changes in both receptors with elevated cholesterol, shifting proximity from transmembrane segment (TM) 3 toward transmembrane segment 5. Of note, cholesterol residence time at this motif is longer for CCK2R than CCK1R and longer in high cholesterol conditions at both receptors. This suggests that the cholesterol sensitivity of CCK1R is likely a dynamic event mediated by short, transient cholesterol interaction with CCK1R under normal conditions. One residue in position 5.52 was critical for this cholesterol effect on CCK1R, despite the prediction that this is not due to direct interaction with cholesterol. Instead, the packing of hydrophobic residues around 5.52 is tighter in CCK1R than in CCK2R, likely affecting the position and movement of transmembrane segment 5 that are important for stimulus-activity coupling. SIGNIFICANCE STATEMENT: Membrane cholesterol can affect the function of select G protein-coupled receptors, such as the type 1 cholecystokinin receptor, that are targets for drugs in disease states in which membrane cholesterol can be elevated. This article studied the molecular basis for high cholesterol disruption of stimulus-activity coupling at this receptor using site-directed mutagenesis and molecular dynamics. The findings demonstrate that cholesterol residence time at a key cholesterol association motif within CCK1R is responsible for this effect.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 10","pages":"100074"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13168989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trace amine-associated receptor 1 agonists differentially regulate dopamine transporter function.","authors":"Julia K Huey, Xiao Shi, William E Schutzer, Aaron Janowsky, Atheir I Abbas","doi":"10.1016/j.molpha.2025.100064","DOIUrl":"10.1016/j.molpha.2025.100064","url":null,"abstract":"<p><p>Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor stimulated by trace amines and amphetamine-like psychostimulants. The TAAR1 agonists RO5166017 and RO5256390 have antidepressant- and anxiolytic-like effects in preclinical models, and the TAAR1/partial 5HT_1A agonist ulotaront has been evaluated for its clinical utility as an antipsychotic. Early clinical investigations of ulotaront for treating psychosis in schizophrenia yielded positive endpoints. However, results from phase III clinical trials showed that ulotaront had the same efficacy as placebo. One concern arising from these results is that investigational TAAR1 agonists could be diverse in the mechanisms by which they influence dopamine homeostasis. Thus, we evaluated the pharmacology of TAAR1 agonists RO5166017, RO5256390, and ulotaront at the dopamine transporter (DAT) and TAAR1 to test our hypothesis that there would be differences among agonists in their effects on DAT. We found that RO5166017 and RO5256390 directly bind DAT and inhibit dopamine uptake, while ulotaront did not. In cultured cells and rodent synaptosomes, pretreatment with ulotaront and RO5256390 reduced dopamine uptake by approximately half, while RO5166017 pretreatment increased dopamine uptake by a similar magnitude. In cells, the effects of TAAR1 agonist pretreatment on dopamine uptake were TAAR1-dependent. RO5166017, but not RO5256390 or ulotaront, increased amphetamine-induced dopamine efflux in a TAAR1-dependent manner. Surface biotinylation experiments indicated that RO5166017 pretreatment increased cell-surface DAT by approximately 15% via a TAAR1-dependent mechanism. These findings demonstrate clinically relevant differences in the effects of 3 TAAR1 agonists on DAT. SIGNIFICANCE STATEMENT: This study evaluated the direct and heterologous TAAR1-dependent effects of the TAAR1 agonists RO5166017, RO5256390, and ulotaront at DAT. All 3 affected DAT transport and/or trafficking, with each exhibiting a unique profile of direct and heterologous effects, some of which were TAAR1-dependent. These issues should be considered with therapeutic design and clinical use of TAAR1 agonists.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 9","pages":"100064"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12597562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pirin does not bind to p65 or regulate NFκB-dependent gene expression but does modulate cellular quercetin levels.","authors":"Melissa Meschkewitz, Erika M Lisabeth, Denaly Anna Cab Gomez, Jeffrey Leipprandt, Richard R Neubig","doi":"10.1016/j.molpha.2025.100070","DOIUrl":"10.1016/j.molpha.2025.100070","url":null,"abstract":"<p><p>Pirin is a nonheme iron-binding protein with a variety of proposed functions, including serving as a coactivator of p65 NFκB and quercetinase activity. We report here, failure to confirm pirin's primary proposed mechanism, binding of Fe(III)-pirin and p65. Analytical size exclusion chromatography and fluorescence polarization studies did not detect an interaction. We also found no effects of pirin on tumor necrosis factor α-activated p65-regulated gene transcription using mouse embryonic fibroblasts from a pirin knockout mouse and a pirin knockdown NIH3T3 fibroblast cell line. Tumor necrosis factor α-activated p65 response gene mRNA was neither increased nor decreased in cells with loss of pirin compared to wild-type (WT) cells. Furthermore, pirin immunofluorescence in NIH3T3 fibroblasts showed primarily a cytoplasmic localization, not nuclear, as in most previous studies. This was confirmed by cell fractionation analysis. Pirin did show colocalization with the endoplasmic reticulum (ER) marker protein disulfide isomerase as well as cyotoplasmic labeling. We confirmed pirin's quercetinase activity in biochemical assays and demonstrated competitive inhibition by the pirin inhibitor, CCG-257081. Cellular quercetin levels in cells exposed to quercetin in vitro were increased by knockdown of pirin or by treatment with pirin inhibitors. Because pirin is localized to the ER and flavanols are protective of ER stress, we investigated whether pirin knockdown altered ER stress signaling, but did not find any effect of pirin knockdown on ER stress response genes. Our results challenge the dominant model of pirin's function (NFκB regulation) but confirm its quercetinase activity with implications for the mechanisms of pirin binding small molecules. SIGNIFICANCE STATEMENT: Pirin has multiple proposed functions and plays an important role in cancer (melanoma, colon, and breast) and inflammatory diseases. Small molecule pirin-binding compounds have been identified, but pirin's functional mechanism remains poorly understood. This study raises doubts about the primary description of pirin as a nuclear regulator of p65 NFκB function but validates pirin's role as a quercetinase. This study shows that pirin-binding compounds can raise cellular quercetin levels. Further studies will be required to fully understand pirin's biological mechanisms.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 9","pages":"100070"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12597533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A machine learning-based analysis method for small molecule high content screening of three-dimensional cancer spheroid morphology.","authors":"Vishakha Goyal, Dvir Blivis, Steven A Titus, Misha Itkin, Alexey Zakharov, Kelli Wilson, Natalia J Martinez, Ty C Voss","doi":"10.1016/j.molpha.2025.100067","DOIUrl":"10.1016/j.molpha.2025.100067","url":null,"abstract":"<p><p>Although multiparameter cellular morphological profiling methods and three-dimensional (3D) biological model systems can potentially provide complex insights for pharmaceutical discovery campaigns, there have been relatively few reports combining these experimental approaches. In this study, we used the U87 glioblastoma cell line grown in a 3D spheroid format to validate a multiparameter cellular morphological profiling screening method. The steps of this approach include 3D spheroid treatment, cell staining, fully automated digital image acquisition, image segmentation, numerical feature extraction, and multiple machine learning approaches for cellular profiling. For comparison, we measured the same samples after live-cell microscopy with an endpoint CellTiter-Glo cell viability assay. The combined method characterized 7 reference compounds with previously reported anticancer/cytotoxic properties that induce quantifiably different spheroid morphologies in this assay. The method was then used to screen a library of 925 compounds that are related to kinase signaling pathways. Both unsupervised and supervised machine learning approaches identified compounds that induced morphologies similar to those induced by the reference compounds. We performed a follow-up 16-point concentration response experiment for 3 of these compounds selected from our profiling pipeline and confirmed their phenotype. The morphology-based concentration response for these compounds was also correlated with the CellTiter-Glo endpoint assay. Additionally, the measured morphological phenotypes displayed different enrichment levels of commonly annotated mechanisms of action. Our analysis was able to identify selected mechanisms of action associated with specific phenotypic signatures. Overall, the presented screening and analysis method can distinguish between different spheroid structural changes that are caused by specific candidate anticancer compounds. SIGNIFICANCE STATEMENT: Morphological profiling has become a powerful tool in the field of microscopy for finding distinct mechanisms of action groups and small molecule screening to identify new phenotypes. This study presents new potential mechanisms of action groups for known glioblastoma candidates from the screening library, which is believed to help advance the search for more effective glioblastoma therapies.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 9","pages":"100067"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12597564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver CYP4A autophagic lysosomal degradation: A major role for the autophagic receptor SQSTM1/p62 through an uncommon target interaction site.","authors":"Liang He, Doyoung Kwon, Michael J Trnka, Yi Liu, Jade Yang, Kathy H Li, Rheem A Totah, Eric F Johnson, Alma L Burlingame, Maria Almira Correia","doi":"10.1016/j.molpha.2025.100061","DOIUrl":"10.1016/j.molpha.2025.100061","url":null,"abstract":"<p><p>The hepatic P450 hemoproteins CYPs 4A are typical N-terminally anchored type I endoplasmic reticulum (ER) proteins, inducible by many hypolipidemic drugs and peroxisome proliferators. They are engaged in the ω-/ω-1-oxidation of various fatty acids including arachidonic acid, prostaglandins, and leukotrienes and in the biotransformation of some therapeutic drugs. Because the proteolytic turnover of the mammalian liver CYPs 4A remains obscure, we have characterized it. We report that of these proteins, human CYP4A11 and mouse Cyp4a12a are preferential targets of the ER-lysosome-associated degradation. Consequently, these proteins are stabilized 2- to 3-fold both as 1%Triton X100-soluble and insoluble species in mouse hepatocytes and HepG2 cells deficient in the autophagic initiation ATG5 gene. Despite exhibiting surface microtubule-associated protein light chain 3-interacting regions that could target them directly to the autophagosome, they nevertheless interact intimately with the autophagic receptor SQSTM1/p62. Through structural deletion analyses and site-directed mutagenesis, we have identified the CYP4A-interacting p62 subdomain to lie between residues 170 and 233, which include its Traf6-binding and LIM-binding subdomains. Mice carrying a liver-specific genetic deletion of p62 residues 69-251 (p62Mut) that includes the CYP4A-interacting subdomain also exhibit Cyp4a-protein stabilization as 1% Triton X100-soluble and insoluble species. Consistently, p62Mut mouse liver microsomes exhibit 1.5- to 2-fold enhanced ω- and ω-1-arachidonic acid hydroxylation to its physiologically active metabolites 19 and 20-HETEs relative to the corresponding wild-type mouse liver microsomes. Collectively, our findings suggest that disruption of CYP4A ER-lysosome-associated degradation results in functionally active P450 protein stabilization and consequent proinflammatory metabolite generation along with insoluble CYP4A aggregates, which may contribute to pathological aggregates, ie, Mallory-Denk bodies/inclusions, hallmarks of many liver diseases. SIGNIFICANCE STATEMENT: Human CYP4A11 and mouse Cyp4a12a, liver P450 enzymes engaged in ω-/ω-1-oxidation of arachidonic acid, prostaglandins, and leukotrienes, are documented to physiologically turn over via endoplasmic reticulum-lysosome-associated autophagic degradation, which involves their intimate association with the autophagic receptor SQSTM1/p62. Genetic endoplasmic reticulum-lysosome-associated autophagic degradation disruption or deletion of their hepatic p62-interaction subdomain in mice results in Cyp4a-protein stabilization as functionally active solubilizable species with consequently enhanced proinflammatory 20-HETE arachidonate metabolite generation and insoluble Cyp4a aggregates, potential contributors to pathologic liver inclusions.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 9","pages":"100061"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12597595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The peroxisome proliferator-activated receptor α/β/γ agonist NCPC-626 from microbial metabolites alleviates metabolic dysfunction-associated steatohepatitis in mice.","authors":"Man Yu, Xiao Ren, Ruolan Li, Wenbin Shen, Baohua Zhao, Yeying Li, Xuelian Zhang, Xiaolan Cui, Jingtong Zhu, Xuexia Zhang, Lijie Wang, Xinhua Lu, Zhihui Zheng","doi":"10.1016/j.molpha.2025.100065","DOIUrl":"10.1016/j.molpha.2025.100065","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by steatosis, inflammatory responses, and fibrosis. Peroxisome proliferator-activated receptors (PPARs), master regulators of glucolipid homeostasis and inflammatory pathways, have emerged as promising therapeutic targets for MASH. PPAR agonists have demonstrated therapeutic potential in MASH by ameliorating hepatic lipid deposition, normalizing dyslipidemia, enhancing insulin sensitivity, and suppressing proinflammatory signaling. In this study, we reported that NCPC-626, a natural fungal metabolite, was discovered as a novel potent pan-PPAR agonist through high-throughput screening. In an in vitro model of MASH, NCPC-626 inhibited lipid accumulation, fibrosis, and inflammation. Moreover, NCPC-626 treatment reduced body weight, liver triglyceride levels, and improved glucose tolerance in db/db mice by regulating glucolipid metabolism. Additionally, NCPC-626 exhibited preventive and therapeutic effects against fibrosis in a CCl₄-induced fibrosis model and ameliorated MASH progression in a diet-induced model. This study highlights NCPC-626 as a pan-PPAR agonist with a novel chemical scaffold for MASH treatment. SIGNIFICANCE STATEMENT: This study identifies a novel structural compound, NCPC-626, demonstrating specific and balanced activation of peroxisome proliferator-activated receptors. NCPC-626 demonstrates therapeutic efficacy against metabolic dysfunction-associated steatohepatitis in experimental models.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 9","pages":"100065"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12597598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biasing G protein βγ subunit downstream signaling enhances the analgesic effects of endogenous opioid receptor agonists during nitroglycerin-induced thermal hypersensitivity.","authors":"Farzanna A Mohamed, Alan V Smrcka, Emily M Jutkiewicz","doi":"10.1016/j.molpha.2025.100068","DOIUrl":"10.1016/j.molpha.2025.100068","url":null,"abstract":"<p><p>μ-Opioid receptor (MOR) agonists are a mainstay in acute pain management. However, they also produce adverse effects and are frequently misused, increasing susceptibility for opioid use disorder. Thus, a strategy for improving the safety of opioid analgesics is needed. Gallein-mediated inhibition of Gβγ signaling to a subset of inhibitory effector feedback systems, such as phospholipase C (PLC) β3 and G protein-coupled receptor kinase 2, potentiates the antinociceptive effects of morphine without altering its rewarding effects in vivo. In this study, we examined effectiveness of gallein in the context of persistent pain using a nitroglycerin (NTG)-induced thermal hypersensitivity assay. In the warm water tail withdrawal assay, NTG (10 mg/kg, i.p.) decreased tail withdrawal latencies by 90%, from 30 to 3 seconds, indicating a hyperalgesic state. Gallein alone fully reversed NTG-induced decreases in withdrawal latencies. Furthermore, a low dose of gallein (3.2 mg/kg, i.p.) that was ineffective alone was sufficient to potentiate the antihyperalgesic effects of morphine. Pretreatment with the nonselective opioid antagonist naloxone (1.0 mg/kg, i.p.) attenuated both the antihyperalgesic effects of gallein alone and gallein-mediated potentiation of morphine. NTG did not decrease tail withdrawal latencies in PLCβ3^-/- mice compared with wild-type littermates, and this apparent antihyperalgesia was also reversed by naloxone. Taken together, the Gβγ inhibitor gallein alone produced antihyperalgesic effects mediated by endogenous opioid receptor activation. These data suggest that inhibiting Gβγ effectors, such as PLCβ3, downstream of MOR activation improves the analgesic effects of both endogenous and exogenous MOR agonists. SIGNIFICANCE STATEMENT: This study demonstrates the potential of small molecule-mediated modulation of Gβγ signaling to enhance the analgesic effects of endogenous opioid peptides suggesting a novel strategy for safer pain management, reducing the risk of opioid use disorder while maintaining effective pain relief.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 9","pages":"100068"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12597591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}