Acta Pharmacologica Sinica最新文献

{"title":"Targeting intrinsic and CAF-mediated signaling by PI3Kα inhibitor CYH33 attenuated metastasis in lung squamous cell carcinoma.","authors":"Xiao-Yu Ma, Jie-Ting Deng, Zhe-Rui Cao, Lan Xu, Jian Ding, Ling-Hua Meng","doi":"10.1038/s41401-025-01719-z","DOIUrl":"10.1038/s41401-025-01719-z","url":null,"abstract":"<p><p>Aberrant activation of PI3K signaling is frequently observed in lung squamous cell carcinoma (LUSC) and is strongly associated with metastasis in advanced-stage patients, but the therapeutic efficacy of PI3K inhibitors and underlying mechanisms in LUSC remain poorly defined. CYH33 is a highly selective PI3Kα inhibitor, which is in phase I/II clinical trials for the therapy of advanced solid tumors including LUSC. In this study, we investigated the efficacy of CYH33 against metastatic LUSC. We showed that CYH33 dose-dependently suppressed the motility of LUSC cells by blocking PI3K signaling and disrupting cytoskeletal structure. Oral administration of CYH33 significantly attenuated the metastasis of orthotopically implanted xenografts derived from LUSC SK-MES-1 cells. RNA-seq and GO enrichment analysis revealed that CYH33 treatment resulted in decreased infiltration of cancer-associated fibroblasts (CAFs) in primary tumors. We demonstrated that CAFs promoted the migration of SK-MES-1 cells by secreting the pro-migratory factors and activating PI3K signaling in tumor cells, which was blocked by CYH33. Moreover, CYH33 concurrently suppressed the trans-differentiation and proliferation of CAFs, thereby reducing the secretion of hepatocyte growth factor (HGF), which likely contributed to its anti-metastatic effect. Consistently, co-inoculation of SK-MES-1 cells with fibroblasts significantly potentiated tumor metastasis in nude mice, whereas CYH33 treatment robustly suppressed this process, accompanied with reduced expression of α-SMA and HGF as well as epithelial-mesenchymal transition (EMT) signature in primary tumor. Furthermore, CYH33 possessed potent activity against the growth of LUSC with hyperactivated PI3K signaling. Collectively, the dual-targeting of CYH33 that directly blocked PI3Kα in tumor cells and disrupted CAF-mediated pro-metastatic signaling supported PI3Kα inhibitors as a potential therapeutic approach for advanced LUSC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1312-1325"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc finger BED-type containing 6 (ZBED6) ameliorates cardiac fibrosis by inhibiting Piezo1 transcription and YAP nuclear translocation.","authors":"Han Wu, Wei-Tao Jiang, Qiao-Yue Zhao, Xin-Yue Zhang, Ping Pang, Chun-Lei Wang, Zhuo Wang, Ke-Ying Lin, Fang-Ting Yao, Kun-Kun Zou, Yu-Ning Zhang, Tian-Qi Duo, Feng Zhang, Ling-Hua Zeng, Wei Si, Xue Kong, Jing-Lun Song, Teng-Fei Pan, Hong-Tao Diao, Bao-Feng Yang, Yu Bian","doi":"10.1038/s41401-025-01717-1","DOIUrl":"10.1038/s41401-025-01717-1","url":null,"abstract":"<p><p>Cardiac fibroblasts progressively replace deceased cardiomyocytes during the development of myocardial fibrosis, an irreversible pathological repair process that ultimately leads to cardiac dysfunction and heart failure. Cardiac injury was evaluated by echocardiography and Masson staining in myocardial  infarction (MI) mice with zinc finger BED-type containing 6 (ZBED6) knockdown or overexpression. Furthermore, chromatin immunoprecipitation (ChIP) assays, electrophoretic mobility shift assays (EMSAs), and luciferase reporter assays were used to explore the target of ZBED6. ZBED6 expression was notably decreased in vivo in MI hearts and in vitro in TGF-β-induced primary mouse cardiac fibroblasts (PMCFs). Transgenic overexpression of ZBED6 specifically in cardiac fibroblasts improved cardiac dysfunction, reduced the infarct area, and decreased the expression levels of fibrotic genes after MI injury. Conversely, physiological knockdown of ZBED6 induced cardiac dysfunction and remodeling, which is consistent with the phenomena observed in vitro. Mechanistically, ZBED6, which functions as a transcriptional inhibitor of Piezo1, failed to prevent its transcription owing to mutations in the promoter binding sites. Stimulation of Piezo1 in PMCFs facilitates YAP translocation into the nucleus, whereas knockdown of Piezo1 or the use of a Piezo1 inhibitor suppresses this translocation. Moreover, the activation of Piezo1 reversed the cardioprotective effects of ZBED6 overexpression. In summary, the protective effect of ZBED6 against myocardial fibrosis injury is achieved through the inhibition of Piezo1 transcription, leading to reduced YAP nuclear translocation. These findings suggest that ZBED6 may become a potential therapeutic target for the clinical treatment of myocardial fibrosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1162-1175"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting RSK2 enhances the efficacy of IGF1R inhibitor against triple-negative breast cancer via antagonizing IGF1/IGF1R signaling mediated by GATA3-IGFBP5 pathway.","authors":"Tian-Jiao Shan, Lan-Ya Li, Xiao-Ya Wan, Yi-Zhi Li, Ting Jiang, Zong-Lin Chen, Xiao-Hui Yu, Yan Cheng","doi":"10.1038/s41401-025-01673-w","DOIUrl":"10.1038/s41401-025-01673-w","url":null,"abstract":"<p><p>Targeting the IGF1 system holds promise as a therapeutic approach for breast cancer. However, the intricate nature of IGF1 signaling and suboptimal drug combinations have resulted in limited clinical success. This study demonstrates that silencing p90 ribosomal S6 kinase 2 (RSK2), a downstream effector of the Ras/ERK pathway, inhibits IGF1 signaling by upregulating the expression and secretion of IGFBP5, a potent inhibitor of the IGF1-IGF1R axis that competes with IGF1 for binding. Mechanistically, GATA3 is identified as a novel transcription factor for IGFBP5, and RSK2 promotes GATA3 degradation by directly binding and phosphorylating it at serine 308, thus suppressing IGFBP5 transcription. Moreover, combined treatment with the RSK2 inhibitor LJH685 and the IGF1R inhibitor PPP significantly reduces metastasis of triple-negative breast cancer (TNBC) in both in vitro and in vivo models. These findings uncover new targets for synergistic antitumor therapy in TNBC and suggest that concurrent inhibition of IGF1R and RSK2 may offer an effective combinatorial treatment strategy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1300-1311"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UBC9-mediated p53 SUMOylation drives tubular senescence and exacerbates acute kidney injury in mice.","authors":"Qi-Mei Wu, Jing Liu, Ying-Song Mu, Juan Li, Ying-Jie Tian, Zhi Wang, Miao Deng, Yang-Mei Qiu, Shu Zhou, Zi-Yang Zhang, Xin-Mei Xu, Liang Ma, Ping Fu, Xiao-Yong Yan, Zhou-Ke Tan","doi":"10.1038/s41401-025-01715-3","DOIUrl":"10.1038/s41401-025-01715-3","url":null,"abstract":"<p><p>The pathogenesis of acute kidney injury (AKI) is closely related to the senescence of renal tubular epithelial cells (RTECs). The role of small ubiquitin-like modification (SUMOylation) in cellular stress and senescence has been gradually elucidated. Recent evidence has demonstrated that SUMOylation of p53 promotes cellular senescence. In this study, we investigated whether p53 SUMOylation-mediated cellular senescence contributes to AKI. A mouse AKI model was established via intraperitoneal injections of cisplatin (20 mg/kg, i.p.). The mice were sacrificed 72 h after the injection, and both blood and kidney tissue were collected. We found that UBC9 (Ube2i), the sole E2-conjugating enzyme for SUMOylation, was significantly upregulated in injured kidneys and drove p53-mediated cellular senescence. Tubular-specific knockdown of Ube2i or administration of the small-molecule UBC9 inhibitor 2-D08 (10 mg/kg, i.p, twice prior to and post-cisplatin injection) markedly alleviated senescence-related marker expression, improved renal function, and attenuated tissue damage in AKI model mice. We demonstrated that UBC9 interacted with p53 and promoted its SUMOylation at lysine 386 (K386). Chromatin immunoprecipitation assays demonstrated that UBC9 enhanced p53 binding to the p21 promoter, whereas the K386R mutation abolished this interaction. These results establish UBC9-mediated p53 SUMOylation as a critical pathway in acute injury-related renal senescence in mice and suggest its potential as a therapeutic target.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1204-1218"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel photosensitizer berberine derivative B12 induces apoptosis and suppresses HIF-1α expression in colorectal cancer cells via mitochondria-to-nucleus sequential-targeting.","authors":"Wen-Bin Pei, Zi-Yu Lei, Fu-Quan Xie, Peng Chen, Yong-Cheng Su, Yu-Shan Qin, Jiang-Quan Li, Qian-Wen Shen, Miao-Miao Ma, Chun-Yi Gao, Jia-Chen Zhu, Ya-Jie Xu, Kai-Yue Zhang, Wen-Qing Zhang, Yan-Dong Zhang, Tian-Hui Hu, Bei-Bei Xu","doi":"10.1038/s41401-025-01728-y","DOIUrl":"10.1038/s41401-025-01728-y","url":null,"abstract":"<p><p>Photodynamic therapy (PDT) boasts the advantages of high spatiotemporal selectivity and non-invasiveness, but its clinical application is still limited by the hypoxic tumor microenvironment and inherent drawbacks of traditional photosensitizers such as aggregation-induced quenching (ACQ), insufficient targeting ability, and systemic toxicity. We previously conducted a structure-activity relationship (SAR) study on a plant-derived alkaloid, berberine, and found that its derivative B12 not only significantly enhanced antitumor efficacy but also improved water solubility and bioavailability. In this study, we characterized the photodynamic properties of B12, investigated its anticancer mechanisms, and evaluated the photodynamic therapeutic efficacy and biosafety of B12 in the tumors of xenograft mouse models. We showed that B12 was a novel photosensitizer without ACQ effect, exhibited both type I and type II photodynamic activities, and generated a large amount of reactive oxygen species (ROS) under both normoxic and hypoxic conditions. In addition, B12 (12.5, 25 μM) significantly enhanced its therapeutic effect against RKO and HCT116 cells in the hypoxic microenvironment by inhibiting the AKT/mTOR signaling pathway and downregulating the expression of hypoxia-inducible factor HIF-1α. In RKO cells, B12 (2 μM) exhibited dynamic dual-organelle-targeting properties after photoactivation: it first induced the collapse of mitochondrial membrane potential, then translocated to the nucleus and bound to DNA. It improved the intersystem crossing (ISC) efficiency by narrowing the singlet-triplet energy gap, thereby amplifying the generation of ROS and damaging DNA integrity. In mice xenografted with B16 cells, intratumoral injection of B12 (5 mg/kg) followed by 10 min light irradiation daily for 9 days significantly suppressed tumor growth with good biosafety. In conclusion, the small molecule B12 simultaneously possesses type I and type II photodynamic activities, dynamic organelle-targeting and hypoxia adaptation properties. This study may provide a reference for the research and design of hypoxia-tolerant small-molecule photosensitizers and break through the clinical bottlenecks of photodynamic therapy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1249-1269"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benchmarking co-folding methods to predict the structures of covalent protein-ligand complexes.","authors":"Tong-Han Zhang, Jin-Tao Zhu, Zhi-Xian Huang, Juan Xie, Jian-Feng Pei, Lu-Hua Lai","doi":"10.1038/s41401-025-01721-5","DOIUrl":"10.1038/s41401-025-01721-5","url":null,"abstract":"<p><p>Targeted covalent inhibitors (TCIs) are emerging as a new modality in drug discovery because of their strong binding affinity and prolonged target engagement. However, the rational design of TCIs remains a significant challenge and is hindered by the lack of methods that accurately predict the structures of covalent protein-ligand complexes. Recent advances in co-folding approaches have made substantial strides in modeling complex biomolecular structures. Despite significant progress, their performance profiles for predicting the structures of covalent protein-ligand complexes remain largely unexplored because of the absence of rigorous benchmarks. Here, we introduce CoFD-Bench, a comprehensive benchmark dataset comprising 218 recently resolved covalent complexes designed to systematically evaluate both classical docking methods (AutoDock-GPU, CovDock, and GNINA) and deep learning co-folding models (AlphaFold3 (AF3), Chai-1, and Boltz-1x). Our results demonstrate that co-folding methods achieve superior ligand RMSD accuracy and protein-ligand interaction recovery. However, their performance markedly declines for novel pocket-ligand pairs. In contrast, classical docking methods exhibit stable but modest performance, which is primarily limited by target conformations. Furthermore, computational efficiency evaluations show that co-folding methods are slower than classical approaches, posing challenges for large-scale predictions. We also reveal that AF3 has the potential to identify native covalent residues through noncovalent co-folding, with a ligand RMSD comparable to that of covalent co-folding. These findings offer a possible route to explore covalent binding without prior specification of reactive residues, which are often unknown in real-world scenarios. Our study provides crucial insights and new opportunities for future co-folding-based TCI design, informing future model applications and improvements. CoFD-Bench offers rigorous evaluation criteria, diverse docking scenarios, and various methodological baselines, positioning it as an important benchmark for future model development and assessment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1374-1384"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI and experimental convergence: a synergistic pathway to JAK2 inhibitor discovery.","authors":"Maryam, Hwangeui Cho, Ankit Pokhrel, Sourav Chandra, Han-Jung Chae, Kil To Chong, Hilal Tayara","doi":"10.1038/s41401-025-01701-9","DOIUrl":"10.1038/s41401-025-01701-9","url":null,"abstract":"<p><p>Janus kinase 2 (JAK2) is an important therapeutic target for various inflammatory diseases, cancers, and rheumatoid arthritis. Therefore, inhibiting JAK2 has become a promising approach for treating these conditions. In this study, molecular descriptors such as Morgan fingerprints, Molecular Access System (MACCS), and PaDEL were calculated and used to develop machine-learning models. Among these models, CatBoost combined with Morgan fingerprints performed the best, achieving an accuracy of 0.94 on the test dataset. This CatBoost model was then used to screen the Korean Chemical Databank (KCB) to identify the most potent JAK2 inhibitors. Computational analyses, including density functional theory (DFT), molecular docking, and molecular dynamics simulations, were carried out to evaluate the performance of the top-ranked molecules. Finally, four compounds were selected for experimental testing, and the results showed that their IC₅₀ values were less than 10 μM. The integration of AI-driven modeling with experimental validation provides a promising strategy for personalized medicine, enabling the development of more precise and effective kinase-targeted therapies while reducing the time and cost required to bring new drugs to clinical trials.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1361-1373"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target.","authors":"Zi-Ning Zhu, Chong-Zhao You, Qing-Ning Yuan, Jiu-Yin Xu, Zong-Yue Gu, Zheng Huang, Miao Liu, Bei Shan, James Jiqi Wang, Wen Hu, Kai Wang, Wan-Chao Yin, You-Wei Xu, H Eric Xu, Can-Rong Wu","doi":"10.1038/s41401-025-01720-6","DOIUrl":"10.1038/s41401-025-01720-6","url":null,"abstract":"<p><p>The global obesity epidemic, affecting over 650 million adults, demands innovative therapeutics. GPR75 has emerged as a promising anti-obesity target, with genetic evidence linking loss-of-function variants to protection against obesity and type 2 diabetes. However, structural insights have remained elusive due to GPR75's inherent expression and stabilization challenges. Here we present the cryo-EM structures of human GPR75 in apo and Gq-coupled states, achieved through advanced stabilization techniques including NanoBiT and molecular glue approaches. Our structures reveal unique architectural features: a completely collapsed extracellular domain eliminates the traditional orthosteric binding pocket, raising critical questions about previously reported small molecule ligands. GPR75 assumes active-like conformation in both apo and G protein complexed structures through unique molecular switches-the canonical DRY motif is replaced by HRL, abolishing the ionic lock, while a distinctive Lys134-Asp210 salt bridge stabilizes the active conformation without ligand binding. This dramatic structural divergence from conventional GPCRs necessitates alternative therapeutic strategies targeting allosteric sites or protein-protein interactions rather than orthosteric pockets. Our findings establish a crucial structural framework for developing next-generation anti-obesity therapeutics.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1351-1360"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morchella polysaccharide ameliorates myocardial infarction inflammation in mice through increasing gut microbiota-derived 12-HEPE.","authors":"Hui-Min Su, Jia-Xin Li, Jun-Fang Wu, Chao Wu, Shi-Hao Sheng, Rui-Si Wang, Zhi-Qing Guo, Shi-Chun Shen, Yun-Fei Gao, Bei-Duo Tian, Dan-Dan Wang, Ping-Ping Wu, Ze-Qun Yin, Ji-E Yang, Ya-Jun Duan, Jun-Bo Ge, Shuang Zhang, Li-Kun Ma","doi":"10.1038/s41401-025-01725-1","DOIUrl":"10.1038/s41401-025-01725-1","url":null,"abstract":"<p><p>Myocardial infarction (MI) initiates robust inflammatory responses. While moderate inflammation facilitates the clearance of necrotic debris, sustained inflammation promotes fibrosis and exacerbates MI progression. Fungal polysaccharides have shown significant anti-inflammatory activity, but role of Morchella polysaccharide (MCP) in modulating MI-associated inflammation remains unclear. In this study we investigated whether MCP ameliorated myocardial infarction injury and elucidated the underlying mechanisms focusing on the gut microbiota and associated metabolites. MI mice were established in mice by permanent ligation of the left anterior descending (LAD) coronary artery. MCP (200, 600 mg·kg^-1·d^-1. i.g.) was administered daily from D7 prior-MI induction and continued for 3 or 7 days post-MI. We showed that MCP administration significantly alleviated cardiac inflammation in post-MI mice. Metabolite screening identified 12-hydroxy-eicosapentaenoic acid (12-HEPE) as a critical mediator of MCP's anti-inflammatory effects. Intestinal metabolomic screening revealed that MCP markedly upregulated the abundance of the beneficial genus Lactobacillus. Eliminating the intestinal flora using a broad-spectrum antibiotic cocktail for 2 weeks abolished MCP-induced 12-HEPE elevation and anti-inflammation in post-MI mice. On the other hand, direct supplementation of 12-HEPE (200 µg·kg^-1·d^-1, i.p.) beginning 7 days prior to MI induction attenuated the inflammation. In conclusion, this study reveals that MCP attenuates post-MI inflammation by enriching beneficial gut bacteria such as Lactobacillus and increasing their metabolite 12-HEPE. MCP improves post-myocardial infarction (post-MI) inflammation and fibrotic repair by modulating gut microbiota and the intestinal lipid metabolite 12-HEPE. MCP treatment increases the abundance of the beneficial gut bacterium Lactobacillus. Concurrently, MCP enhances the activity of metabolic enzymes responsible for 12-HEPE synthesis within the improved intestinal microenvironment. This elevates intestinal 12-HEPE production and enhances its systemic circulation. Ultimately, increased serum 12-HPE levels attenuate cardiac inflammation and improve injury repair.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1176-1190"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G protein-dependent dopamine D2 receptor signaling mediates cocaine-primed reinstatement.","authors":"Hai-Bo Li, Yong-Hui Liu, Hai Liu, Yuan Li, Qiu-Min Le, Fei-Fei Wang, Lan Ma, Xing Liu","doi":"10.1038/s41401-025-01700-w","DOIUrl":"10.1038/s41401-025-01700-w","url":null,"abstract":"<p><p>The high relapse rate of drugs is currently a therapeutic dilemma in the treatment of substance use disorder (SUD). Emerging evidence from preclinical animal models demonstrates that pretreatment with selective dopamine D₂ receptor (D₂R) antagonists prevents reinstatement of drug-seeking. However, the role of D₂R downstream signaling in regulating relapse behavior remains unclear. In this study, we investigated the roles of G_αi-protein- and β-arrestin-dependent D₂R signaling pathways in cocaine-primed reinstatement using cocaine self-administration (SA) mouse model treated with biased ligands. We found that treatment of D₂R G_αi-protein antagonists, but not β-arrestin antagonists, significantly attenuated cocaine-primed reinstatement of drug seeking without affecting locomotor activity or anxiety levels. Administration of D₂R G_αi-protein antagonists, but not β-arrestin antagonists, increased cyclic adenosine monophosphate (cAMP) levels in the nucleus accumbens (NAc). Furthermore, treatment of D₂R G_αi-protein antagonists, but not β-arrestin antagonists, suppressed cocaine-induced neuronal activation in the NAc. Our results demonstrate that G_αi-protein-dependent D₂R signaling plays a crucial role in cocaine-primed reinstatement and suggest that D₂R G_αi-protein-biased ligands may be promising pharmacotherapeutic targets for SUD treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1117-1131"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145970340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}