Biochemical pharmacology最新文献

{"title":"A novel phosphodiesterase 5 inhibitor, CPD1, alleviates liver fibrosis by modulating the Akt/NF-κB pathway to inhibit activated hepatic stellate cells.","authors":"Wenbin Feng, Jianqin Yang, Jiaxiu Lei, Limei Li, Changfeng Shan, Shenjie Chen, Zongmeng Zhang, Zhenggang Zhao, Sujin Zhou, Allan Zijian Zhao, Yunping Mu, Fanghong Li","doi":"10.1016/j.bcp.2025.117388","DOIUrl":"10.1016/j.bcp.2025.117388","url":null,"abstract":"<p><p>Hepatic fibrosis is a progressive disorder marked by abnormal extracellular matrix buildup, with no effective antifibrotic drugs currently available. Recent evidence indicates that inhibiting phosphodiesterase 5 (PDE5) can have significant benefits for fibrotic diseases, suggesting PDE5 inhibitors may be effective antifibrotic agents. This study aimed to develop a new PDE5 inhibitor, potassium salt crystal form B (CPD1), which has much greater aqueous solubility than sildenafil. We assessed CPD1's efficacy in inhibiting hepatic stellate cells (HSCs) activation and investigated its mechanism of action. The therapeutic effect of CPD1 was studied in a carbon tetrachloride-induced liver fibrosis model, exploring its antifibrotic mechanisms via cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG1) or Akt inhibitors and PKG1 overexpression in LX-2 cells. As anticipated, the expression of PDE5A was significantly elevated in both human and mouse fibrotic liver tissues, as well as in LX-2 cells induced by transforming growth factor-beta 1 (TGFβ1). In vivo, CPD1 reduced serum transaminases in a dose-dependent manner, mitigated liver damage, decreased collagen deposition, and suppressed the activation of HSCs. Additionally, CPD1 is more effective than sildenafil at a lower dosage. In vitro, CPD1 inhibited TGFβ1-induced activation of LX-2 and reduced the expression of fibrotic marker proteins and genes. Notably, the anti-fibrotic effects of CPD1 were completely negated following the administration of a PKG1 inhibitor. Mechanistically, the CPD1 intervention effectively countered the TGFβ1-induced increase in p-IκBα and p-P65. This study demonstrated that CPD1 mitigates liver fibrosis by activating the cGMP/PKG pathway, which in turn inhibits the AKT/NF-κB pathway. Therefore, it may be considered a potential therapeutic agent that warrants further investigation for the treatment of liver fibrosis.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117388"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231477","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":"Defining the role of 12-lipoxygenase in regulating platelet-derived extracellular vesicles.","authors":"Alexis J Matthew, Jaël D Richard, Vanessa L Gauvin, Mathieu P A Hébert, Mohamed Touaibia, Eric P Allain, Luc H Boudreau","doi":"10.1016/j.bcp.2025.117404","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117404","url":null,"abstract":"<p><p>Platelets are traditionally recognized for their role in hemostasis and wound repair, yet they also play a pivotal role in intercellular communication through the release of platelet-derived extracellular vesicles (PMVs). These vesicles contribute to diverse physiological and pathological processes, but the mechanisms governing their biogenesis remain incompletely understood. One candidate regulator is 12-lipoxygenase (12-LO), an enzyme that metabolizes arachidonic acid into the lipid mediator 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). While 12-LO has been linked to coagulation and neutrophil interactions, its involvement in PMV production has not been clearly defined. In this study, we investigated the role of 12-LO in PMV biogenesis using both human and murine platelet models. Pharmacological inhibition of 12-LO significantly reduced 12(S)-HETE levels and PMV release in activated human platelets. Similarly, platelets from 12-LO-deficient (Alox12^-/^-) mice exhibited markedly impaired PMV production upon stimulation. Subpopulation analyses revealed agonist-specific effects of 12-LO deficiency on distinct PMV subsets, including mitochondrial-containing vesicles. Importantly, supplementation with exogenous 12(S)-HETE partially restored PMV production in Alox12^-/^- platelets, confirming the functional relevance of this lipid mediator. Together, these findings identify 12-LO as a critical regulator of PMV biogenesis and suggest that the 12-LO/12(S)-HETE axis represents a novel therapeutic target in inflammatory and thrombotic disorders.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117404"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231501","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":"Theaflavin reduces Achilles tendon heterotopic ossification in mice through the TGF-β/Smad signaling pathway.","authors":"Yuan Li, Chenglong Li, Wensheng Zhang, Shiyong Le, Jiongjiong Zhou, Bijun Luo, Pusheng Xie, Bo Yan","doi":"10.1016/j.bcp.2025.117387","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117387","url":null,"abstract":"<p><p>Heterotopic ossification (HO) affects millions of people worldwide. TGF-β/Smad signaling pathway plays an essential role in HO of the Achilles tendon. Recent studies have found that Theaflavin can regulate the TGF-β/Smad signaling pathway, suggesting Theaflavin may have a positive effect on HO. In this study, we aimed to study the effects of Theaflavin on preventing endochondral differentiation of Tendon-derived stem cells (TDSCs) and the HO process after the achilles tendon injury model. Here, we investigated the role of Theaflavin in a mouse model of Achilles tendon heterotopic ossification. In addition, we use TDSCs to explore the molecular mechanism of Theaflavin affecting HO. Our data showed that Theaflavin can inhibit HO of the Achilles tendon and significantly reduce the volume of mature bone tissues. SOX9 and RUNX2 were decreased significantly after Theaflavin administration. Experiments showed Theaflavin inhibited TGF-β/Smad signaling pathway during chondrogenic differentiation and osteogenic differentiation of TDSCs. Surface Plasmon Resonance Assay and Molecular docking simulation showed that a direct molecular interaction between Theaflavin and TβRI (a membrane receptor of TGF-βs). Meanwhile, Cellular Thermal Shift Assay showed Theaflavin bonded and thermally stabilized TβRI significantly. Moreover, WB and IHC displayed Theaflavin also exhibited inhibitory effects on TβRI phosphorylation. In summary, Our findings demonstrated that TF inhibited HO by down-regulating the TGF-β/Smad signal pathway, and this effect may attributed to TF binded directly to TβRI and prevented its phosphorylation.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117387"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231519","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":"Tissue-specific regulation of NO-GC isoforms in the cardiovascular system.","authors":"Jan Giesen, Lukas Menges, Ralf A Benndorf","doi":"10.1016/j.bcp.2025.117384","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117384","url":null,"abstract":"<p><p>Due to its involvement in the regulation of smooth muscle relaxation, platelet aggregation, and endothelial homeostasis, the nitric oxide (NO) / cyclic guanosine monophosphate (cGMP) cascade plays an important role in cardiovascular health and disease. Cyclic GMP is formed by NO-sensitive guanylyl cyclases (NO-GCs) in response to stimulation by NO. It is also thought that cGMP signaling is influenced by other signaling cascades and hormonal mediators. Interestingly, there is evidence that these interactions are altered by various diseases. In addition, the NO/cGMP signaling pathway is modified by the regulation of effector molecules at the transcriptional and post-transcriptional level, as well as by cellular communication via gap junctions or multidrug resistance-associated proteins. In this context, the use of mouse models and state-of-the-art technologies (e.g., gene targeting or fluorescent indicators) has provided valuable insights into the molecular physiology of cGMP-related signaling processes. Stimulators of NO-GCs and inhibitors of cGMP-degrading enzymes have also found their way into the treatment of chronic heart failure, erectile dysfunction, coronary heart disease, and pulmonary hypertension. Nevertheless, it is still elusive whether cGMP is exclusively beneficial in cardiovascular diseases at the cellular and molecular level. Therefore, a better understanding of cGMP signaling pathways is important for the development of appropriate new therapeutic strategies based on the modification of cGMP levels in the heart and blood vessels. This review article therefore aims to provide an overview of the most important findings of cGMP research in the cardiovascular system and to summarize the known interactions of the system with other relevant cardiovascular mediators in health and disease.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117384"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231534","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":"In Vivo/In vitro metabolic profiling and evaluation of key metabolites of QO-83, a novel KCNQ channel opener with antiepileptic potential.","authors":"Le Yang, Xiaoguang Zhang, Jiaxin Wang, Yixuan Guo, Bingsen Qi, Ziyi Liu, Jingcun Sun, Jinlong Qi","doi":"10.1016/j.bcp.2025.117381","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117381","url":null,"abstract":"<p><p>KCNQ2/3 voltage-gated potassium channels constitute validated therapeutic targets for epilepsy by regulating neuronal hyperexcitability. QO-83, a novel KCNQ channel opener exhibiting potent activity and channel subtype selectivity, was undergoing preclinical studies as an antiepileptic candidate drug. This study integrated in vivo metabolism studies in rats and Beagles with in vitro models of human and rat hepatic systems using liquid chromatography-mass spectrometry (LC-MS). Key metabolites were further evaluated for channel open activity in cells and pharmacokinetics/pharmacodynamics (PK/PD) and safety in animals. The results showed that QO-83 underwent extensive phase I/II metabolism across species, primarily via ketone conjugation, hydroxylation, acetylation, and glucuronidation. Four major metabolites (M1, M2, M8, M19) were identified, with species-specific differences in M8 production. Notably, M8, as the key metabolites of compound QO-83, generated through a relatively rare acetylation phase II metabolic pathway, which may also be the reason for the species-specific differences in metabolism. M8 exhibited significant anticonvulsant activity (ED₅₀ = 9.40 ± 1.98 mg/kg) in the maximal electroshock seizure (MES) model and favorable pharmacokinetics in rats, including near-complete oral absorption (Fabs = 98.7 %). Additionally, acute toxicity assessments revealed a wide safety margin for M8. These findings elucidated the metabolic fate of QO-83 and established M8 as an active metabolite contributing to the antiepileptic efficacy while providing critical data for preclinical safety assessment.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117381"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231502","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":"Inhibition of integrin alpha V reduces inflammation and the transition to heart failure after pressure overload.","authors":"Clément Delacroix, Alexandra Achab-Ali, Paul Alayrac, Marine Gandon-Renard, Aïcha Ben Zemzem, Charlène Jouve, Feriel Hamidou, Morgane Aubert, David Sassoon, Jean-Sébastien Silvestre, Clément Cochain, Stéphane Camus, Jean-Sébastien Hulot","doi":"10.1016/j.bcp.2025.117393","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117393","url":null,"abstract":"<p><p>Integrin alpha V (CD51) is a surface receptor that binds to extracellular matrix ligands and contributes to fibrotic responses, including post-infarction myocardial fibrosis. However, its role in other forms of heart failure, particularly pressure overload-induced cardiac remodeling, remains poorly understood. This study aimed to investigate the role of CD51 in cardiac remodeling and fibrosis under pressure overload conditions and to assess the therapeutic potential of CD51 inhibition in preventing heart failure progression. Two murine pressure-overload models were established using osmotic minipumps delivering either angiotensin II (AngII) alone or in combination with phenylephrine (PE). CD51 expression and CD51⁺ cell infiltration were analyzed, and the functional relevance was tested using the CD51 inhibitor cilengitide. Both models induced comparable hypertrophic remodeling at the organ and cardiomyocytes levels. However, only AngII + PE treatment resulted in significant cardiac fibrosis and pulmonary congestion, along with increased myocardial CD51 expression and CD51⁺ cell infiltration, findings not observed in the AngII-only group. CD51 expression was enriched in a subset of circulating monocytes expressing high levels of MHCII (MHCII^hi), and AngII + PE-treated hearts exhibited increased monocyte infiltration. Daily cilengitide administration significantly reduced cardiac fibrosis, limited heart failure progression, and decreased both CD51 expression in MHCII^hi monocytes and monocyte infiltration into the myocardium, independent of CCR2. CD51 contributes to the immune-fibrotic axis driving heart failure progression under pressure overload. Pharmacological inhibition of CD51 reduces cardiac fibrosis and dysfunction while modulating pro-inflammatory CD51⁺ myeloid cells, offering a novel therapeutic strategy for pressure overload-induced heart failure.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117393"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231511","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":"Neurensin-2 is a negative regulator of CB1 receptor","authors":"Yumna Abu Ghanem,&nbsp;Liora Dorfman-Yahad,&nbsp;Hadas Catane Hovav,&nbsp;Laila Agbariya,&nbsp;Adi Cohen,&nbsp;Hila Yehuda,&nbsp;Gali Umschweif","doi":"10.1016/j.bcp.2025.117382","DOIUrl":"10.1016/j.bcp.2025.117382","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a leading cause of disability worldwide. Unfortunately, approximately 30 % of MDD patients do not respond to available antidepressants, and characterization of novel molecular mediators of MDD is urgently needed. Chronic stress, a key risk factor for MDD, induces widespread neurobiological changes, including alterations in synaptic plasticity and neurotransmission. However, the molecular mechanisms mediating these effects remain poorly defined.</div><div>In this study, we provide evidence that Neurensin-2, a stress-inducible vesicular protein, regulates the cannabinoid receptor 1 (CB1R), an important mediator of depression. In N2a cells, overexpression of Neurensin-2 was associated with reduced CB1R expression and attenuation of its downstream signaling; the Akt, mTOR, and Erk1/2 pathways. In these cells, Neurensin-2 co-localized with CB1R and reduced the expression of this receptor in both the membrane and intracellular organelles. The Neurensin-2-CB1R relationship was examined <em>in vivo</em> using the chronic social defeat stress (CSDS) model, where stress exposure was accompanied by increased <em>Nrsn2</em> and decreased <em>Cnr1</em> expression in the mouse hippocampus. Notably, stress-induced <em>C</em>nr1 downregulation was not observed in Neurensin-2 knockout mice, suggesting that Neurensin-2 plays a role in stress-induced downregulation of CB1R <em>in vivo</em>. We further confirmed these expression patterns within the hippocampal inhibitory neuronal population that highly co-expresses Neurensin-2 and CB1R, the CCK-positive hippocampal interneurons.</div><div>These findings uncover a novel stress-induced pathway that inhibits CB1R signaling by Neurensin-2. Thus, we suggest that Neurensin-2 is a potential therapeutic target for treatment-resistant depression.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117382"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231561","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":"Curcumin reverses irinotecan-acquired resistance in DLD1 colorectal cancer cells: Insights from whole transcriptomic data.","authors":"Laura Gavrilas, Oana Sava, Loredana Balacescu, Stefan Miron, Doina Miere, Ovidiu Balacescu, Cruceriu Daniel","doi":"10.1016/j.bcp.2025.117386","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117386","url":null,"abstract":"<p><p>Acquired resistance to chemotherapy, including irinotecan, remains a major challenge in treating metastatic colorectal cancer (CRC). Natural compounds such as curcumin have demonstrated potential in resensitizing chemoresistant cancer cells to existing therapies. This study investigates curcumin's ability to reverse irinotecan resistance in CRC cells and the underlying molecular mechanisms. An irinotecan-resistant CRC cell line (DLD1_IRI-R) was established by gradually increasing irinotecan exposure. The DLD1 cell line was selected for its intermediate sensitivity to irinotecan among CRC cell lines. Cell sensitivity to irinotecan and curcumin was assessed using the MTT assay, with drug interactions evaluated via the Chou-Talalay method. Apoptosis and cell cycle progression were analyzed by flow cytometry, proliferation by clonogenic assays, and migration in 3D microfluidic systems. Whole-genome transcription profiling was conducted using microarrays, with functional analysis performed in Ingenuity Pathway Analysis. DLD1_IRI-R cells exhibited a 7.17-fold increase in irinotecan resistance, accompanied by reduced proliferation and migration. Resistance acquisition led to dysregulation of genes involved in irinotecan metabolism (CYPs, UGTs, AKRs), efflux transport (ABCs), and ER stress adaptation. The gene coding for the drug target, TOP1, was also inhibited. Curcumin, combined with irinotecan at IC₁₀, reduced irinotecan's IC₅₀ by 3.74-fold, exhibiting strong synergy. Curcumin significantly modulated 3,901 genes (FC > |±2|), inducing apoptosis, disrupting ER stress adaptation, reducing proliferation, and inhibiting migration. It also upregulated TOP1 while suppressing key resistance-associated genes, including 18 CYPs, 4 UGTs, 4 AKRs, and 20 ABCs. These findings suggest that low-dose curcumin effectively reverses irinotecan resistance in CRC cells, enhancing chemotherapy sensitivity and inhibiting metastasis-associated traits.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117386"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231503","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":"Regulation of endothelin receptor expression by microRNAs in diabetes related erectile dysfunction.","authors":"Haibo Li, Jinwei You, Jiao Cang, Yanchufei Zhang, Yuanfang Xiang, Chenchen Yu, Lianjun Pan, Qipeng Zhang, Feng Pan","doi":"10.1016/j.bcp.2025.117397","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117397","url":null,"abstract":"<p><p>Erectile dysfunction (ED) is one of the common complications of type 2 diabetes mellitus (T2DM), feathered by a complex vascular and endothelial pathogenesis and limited therapeutic options. Endothelin receptor type A (ETA), a key receptor for endothelin, mediates chronic and persistent contractile effects in the penile corpus cavernosum (CC), and is a potential target for ED treatment. Dysregulated microRNAs (miRNAs) have been implicated in the pathophysiology of ED, playing critical regulatory roles and suitable for drug development. This study investigates the role of dysregulated miRNAs in regulating the endothelin receptor type A gene (EDNRA) in T2DMED. We found that ETA levels were significantly higher in the CCs of T2DMED rats. Using artificial intelligence (AI)-assisted prediction algorithms, potential miRNAs targeting EDNRA were identified, and miRNA expression profiles in the CCs of control and T2DMED rats were analyzed using RNA-chip technology and testified by quantitative Polymerase Chain Reaction (qPCR). As a result, miR-30-5p and its families, miR-96-5p, and miR-27a-3p were significantly downregulated in the T2DMED group. Luciferase assays confirmed the inhibitory role of these miRNAs on the 3'-untranslated region (3'-UTR) of EDNRA. Hypoxia, a fundamental pathogenic factor in T2DMED, was shown to suppress miRNA expression and increase ETA expression in vitro in penile smooth muscle cells. Additionally, local lentiviral delivery of miR-30-5p in vivo significantly reduced ETA levels in the CCs of T2DMED rats and restored erectile function. In conclusion, downregulated miRNAs contribute to T2DMED pathogenesis by upregulating ETA expression. Targeting EDNRA-regulating miRNAs could offer a novel therapeutic approach for T2DMED.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117397"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231564","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 CREB1/p300-mediated RGS1 expression in tumor-associated macrophages improves the efficacy of anti-PD-1 therapy in triple-negative breast cancer.","authors":"Xiangyu Liu, Xinyan Ju, Ronghui Yuan, Bingxue Pan, Tongtong Feng, Jingjing Ge, Mengdi Wan, Xiaoqian Li, Fei Pan","doi":"10.1016/j.bcp.2025.117395","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117395","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive phenotype of breast cancer with poor prognosis. Immunotherapy, including anti-programmed cell death protein 1 (anti-PD-1) therapy, has shown promise in treating TNBC. This study investigates the impact of regulator of G protein signaling 1 (RGS1) on the efficacy of anti-PD-1 therapy in TNBC patients. Bioinformatics analyses were conducted to analyze differentially expressed genes in tissue-resident macrophages. Functional assays, including Transwell migration, co-culture experiments, quantitative polymerase chain reaction, and cytokine production, were conducted to evaluate the impact of RGS1 on macrophage function and CD8⁺ T cell activity. Chromatin immunoprecipitation and luciferase assays were utilized to determine the regulatory mechanisms of RGS1 expression. RGS1 was upregulated in TNBC patients and specifically in tumor-associated macrophages (TAMs). RGS1 knockdown in M2 macrophages reduced their chemotactic migration when co-cultured with cancer cells. In vivo, RGS1 knockdown in mice sensitized tumors to anti-PD-1 therapy, leading to reduced tumor growth and metastasis, elevated CD8⁺ T cell infiltration, and prolonged survival. cAMP responsive element binding protein 1 (CREB1) and p300 were identified as key regulators of RGS1 expression, and their inhibition impaired M2 macrophage function, enhancing CD8⁺ T cell activity. The effects of CREB1/p300 blockade were negated upon RGS1 overexpression. In conclusion, this study suggests that RGS1 is critical in maintaining the M2 phenotype of macrophage and reducing the efficacy of anti-PD-1 therapy in TNBC. Targeting RGS1 in TAMs may refine the efficacy of immune checkpoint blockade and improve clinical outcomes for TNBC patients. The regulatory mechanisms involving CREB1 and p300 offer potential therapeutic targets for modulating RGS1 expression and TAM function.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117395"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231604","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}