Biochemical pharmacology最新文献

{"title":"Sparfloxacin ameliorates DSS-induced ulcerative colitis by suppressing cellular senescence, JAK/NF-κB signaling pathway and modulation of the gut microbiota-metabolite axis","authors":"Shujia Song ,&nbsp;Fuxing Li ,&nbsp;Bingxiang Zhao ,&nbsp;Yaxing Xu ,&nbsp;Zhenlin Liu ,&nbsp;Jiayu Liu ,&nbsp;Qinran Hou ,&nbsp;Jiale Chen ,&nbsp;Mengting Chen ,&nbsp;Zhengze Liu ,&nbsp;Min Zhou ,&nbsp;Xiaojian Wu ,&nbsp;Xiaobo Wang","doi":"10.1016/j.bcp.2025.117167","DOIUrl":"10.1016/j.bcp.2025.117167","url":null,"abstract":"<div><div>The progression of ulcerative colitis (UC) involves immune dysregulation, intestinal barrier dysfunction, and microbial dysbiosis while existing targeted therapies present challenges, including adverse effects and economic burdens. UC is characterized by persistent intestinal inflammation, manifesting as abdominal pain, hematochezia, and malnutrition. Prolonged uncontrolled inflammation may lead to colorectal cancer or severe complications, significantly impairing quality of life. Recent studies have revealed a significant correlation between pathological accumulation of senescent cells and UC pathogenesis, suggesting anti-senescence therapeutics as potential interventions. In this study, we identified sparfloxacin (SPA), a fluoroquinolone antibiotic, through high-throughput screening as an effective senolytic agent that markedly alleviates DSS-induced murine colitis. Mechanistically, combining cellular and animal experiments with transcriptomic, untargeted metabolomic, and metagenomic analyses, we demonstrated sparfloxacin’s tripartite therapeutic effects: ① Senescence inhibition via downregulation of p16/p21 expression; ② Effective suppression of aberrant JAK/NF-κB signaling activation with a concomitant reduction in pro-inflammatory cytokines (TNF-α, IL-6); ③ Gut microbiota remodeling characterized by increased probiotic abundance and elevated levels of beneficial metabolites. This study for the first time elucidates the molecular mechanism whereby SPA ameliorates UC through coordinated multi-target actions involving senescence inhibition, anti-inflammatory effects, and microbiome restoration. Our findings not only expand the clinical applications of fluoroquinolones but also provide a theoretical foundation for developing integrated UC treatment strategies targeting cellular senescence.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"241 ","pages":"Article 117167"},"PeriodicalIF":5.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633667","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":"Asiaticoside and asiatic acid improve diabetic nephropathy by restoring podocyte autophagy and improving gut microbiota dysbiosis.","authors":"Yinhua Ni, Yuxiang Pan, Jun Zhou, Haimei Du, Wenlong Yang, Liujie Zheng, Yifan Zheng, Haojie Jin, Zhengwei Fu, Cheguo Cai, Qiang He, Juan Jin","doi":"10.1016/j.bcp.2025.117161","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117161","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is a common and severe complication of diabetes. Despite the availability of several drugs for the treatment of DN, there remains a need for novel therapeutic agents with more favorable risk profiles. Asiaticoside (AT) and asiatic acid (AA), two bioactive constituents derived from Centella asiatica, have exerted excellent anti-inflammatory properties. However, the effect and underlying mechanism of AT and AA on DN remains unclear. To investigate the effect and underlying mechanism of AT and AA on DN in mice, a high-fat diet- and streptozotocin-induced diabetic mice model was constructed to induce DN symptoms. AT and AA were then administered for 6 weeks to determine their impact on the progression of DN. The results indicated that AT and AA treatment improved insulin resistance and lipid metabolism while reducing inflammation in the liver and adipose tissue of DN mice. Additionally, AT and AA protected kidney function and alleviated kidney inflammation and fibrosis. Mechanistically, AT and AA mitigated podocyte damage by activating autophagy, and these effects were abrogated after autophagy was inhibited by 3-methyladenine in vitro. AT and AA treatment protected gut barrier function, altered microbial composition and metabolites, and resulted in a reciprocal increase in beneficial bacteria and metabolites and a decrease in harmful ones. In summary, AT and AA administration ameliorated the progression of DN by activating podocyte autophagy and regulating microbiota dysbiosis, laying a theoretical basis for the nutritional intervention of AT and AA in DN.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117161"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636074","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":"Time-dependent inactivation of human cytochrome P450 2A6 variants and 2A13 by imperatorin: natural coumarins and imperatorin oxidation.","authors":"Yune-Fang Ueng, Jia-Shan Chih, Wen-Tai Li, An-Chi Chen, Keng-Chang Tsai, Chia-Ching Liaw, Kaun-Wen Chen, Pei-Syuan Chen, Chu Lin Hsiao","doi":"10.1016/j.bcp.2025.117155","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117155","url":null,"abstract":"<p><p>Structurally diverse coumarins such as imperatorin are widely distributed in edible and medicinal plants. This study aimed to investigate the genotype-associated time-dependent inhibition (TDI) induced by 13 natural coumarins and the mechanism of potent TDI by imperatorin in recombinant systems of human cytochrome P450 (CYP) 2A6 variants and CYP2A13. Compared with psoralen, the addition of methoxy and alkenyl groups enhanced the metabolism-dependent inhibition of the wild type CYP2A6.1. Hydroxylated furanocoumarins, alloisoimperatorin, 5-methoxy-8-hydroxypsoralen, and xanthotoxol, inhibited CYP2A13 but not CYP2A6.1. Imperatorin, which carries a prenyloxy group, strongly inhibited CYP2A6.1/2A13, whereas CYP2A6.10 was less affected. Unlike imperatorin, angelicin inhibited CYP2A6.10 more potently than CYP2A6.1. The imperatorin-induced TDI of CYP2A6.1/2A13 was reduced by glutathione conjugation, but not by dialysis or potassium ferricyanide. Imperatorin oxidation generated a metabolite-intermediate complex with CYP2A6.1. Imperatorin exerted a 33% higher inactivation efficiency with CYP2A13 than that with CYP2A6.1, consistent with the 4-fold higher furanyl epoxidation efficiency of CYP2A13 compared to CYP2A6.1. However, the furanyl epoxidation efficiency of CYP2A6.10 was 18% that of CYP2A6.1. The best docking model revealed that the prenyloxy moiety of imperatorin was located close to the heme group in CYP2A13, but not in CYP2A6.1, which supported the higher efficiency of imperatorin 14-hydroxylation by CYP2A13. In summary, coumarins exhibited differential time-dependence, isoform preference, and variant resistance in CYP2A6/2A13 inhibition. Imperatorin inhibited CYP2A13 and CYP2A6.10 to greater and lesser extents, respectively, than CYP2A6.1, depending on furanyl epoxidation efficiency. Structure-dependent and genotype-associated inhibition of CYP2As by coumarins should be considered in further benefit/toxicity evaluations.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117155"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636021","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":"Gut microbiota and glycochenodeoxycholic role in liver metastasis of breast cancer","authors":"Liping Yan ,&nbsp;Qixing Tan ,&nbsp;Jia Zhu ,&nbsp;Yongfei He ,&nbsp;Peng Tao ,&nbsp;Jianxin He","doi":"10.1016/j.bcp.2025.117128","DOIUrl":"10.1016/j.bcp.2025.117128","url":null,"abstract":"<div><div>Breast cancer liver metastasis presents a significant clinical challenge, requiring a deeper understanding of its underlying mechanisms. In this study, we explored the role of serum metabolites and gut microbiota in breast cancer liver metastasis, with a particular focus on the effects of glycochenodeoxycholic acid sodium salt (GCDC). Serum metabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS), while gut microbiota composition was assessed through 16S rDNA sequencing of stool samples. Statistical analyses revealed a strong correlation between gut microbiota and GCDC levels, which varied markedly among breast cancer, breast cancer liver metastasis, and healthy control groups. GCDC was identified as a microbiota-related metabolite through high-throughput bioinformatics screening. In vitro experiments showed that GCDC inhibited breast cancer cell proliferation, migration, and invasion while inducing cell death. In vivo, GCDC treatment reduced subcutaneous tumor growth and prevented liver metastases, as evidenced by decreased Ki67 expression in tumor tissues. These findings suggested that GCDC suppresses breast cancer liver metastasis by inhibiting cancer cell growth and migration, underscoring its potential as a biomarker for early detection and a therapeutic agent for liver metastasis in patients with breast cancer. Further research is needed to clarify its mechanisms and explore its clinical applications.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"241 ","pages":"Article 117128"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144623609","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":"Adaptively increased intake of arginine sustains oral keratinocyte survival through alleviating oxidative stress during targeting glutamine metabolism.","authors":"Chao Lv, Haoan He, Mi Lin, Wei Li, Wenxin Mu, Bin Cheng, Xiaoan Tao","doi":"10.1016/j.bcp.2025.117165","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117165","url":null,"abstract":"<p><p>Glutamine is a crucial amino acid with a variety of important roles in both health and disease, with ASCT2 (alanine-serine-cysteine transporter 2)-mediated uptake being critical for cellular homeostasis. While ASCT2 inhibition has been proposed as a therapeutic strategy for oral malignancies, our prior work revealed its paradoxical pro-tumorigenic effects in oral squamous cell carcinoma (OSCC), underscoring the complexity of glutamine metabolism targeting. Here, we identify a compensatory arginine-dependent survival mechanism in oral epithelial cells under glutamine restriction. ASCT2-knockout mice exhibit homeostasis in proliferation and apoptosis through SLC7A2 (solute carrier family 7 member 2) upregulation, a process driven by ROS/NF-κB signaling. Increased intracellular arginine serves as an effector for mTOR/S6 activation to promote cell growth in response to glutamine restriction. Additionally, arginine uptake could effectively alleviate oxidative stress and reduce cell apoptosis via the synthesis of glutathione (GSH) and the activation of NRF2/HO-1 signaling upon ASCT2 knockdown. These results not only delineate the metabolic reprogramming cascade mediated through ASCT2 suppression, but more importantly, reveal a clinically actionable strategy of dual glutamine-arginine metabolic intervention with translational promise for overcoming therapy resistance across multiple pathological states, particularly in malignancies exhibiting metabolic plasticity.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117165"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636073","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":"BDH2 promotes GLIPR1 promoter methylation and thus increases 5-FU sensitivity in colorectal cancer.","authors":"Dapeng Lu, Lin Ma, Qingyue Zhang, Chengzhong Xing, Yanke Li","doi":"10.1016/j.bcp.2025.117153","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117153","url":null,"abstract":"<p><p>5-Fluorouracil (5-FU) is an effective drug in the treatment of colorectal cancer (CRC); however, the development of acquired resistance to 5-FU poses a great challenge in clinical practice. Through the analysis of public datasets, we found that reduced 3-Hydroxybutyrate Dehydrogenase 2 (BDH2) expression in CRC tissues predicted poor survival in CRC patients. Low expression of BDH2 in clinical CRC tissue samples predicted a higher degree of malignancy. In addition, public dataset analysis showed that GLI Pathogenesis Related 1 (GLIPR1) expression was elevated in CRC patients following 5-FU treatment, contrasting with the expression pattern of BDH2. We reported that in 5-FU-resistant CRC cell lines (LOVO/5-FU and HCT15/5-FU), BDH2 was downregulated, while the expression of GLIPR1 was increased. To explore the regulatory relationship between BDH2 and GLIPR1 in 5-FU resistance, BDH2 and GLIPR1 overexpression plasmid vectors were constructed to transfect 5-FU resistant CRC cell lines. BDH2 led to enhanced 5-FU sensitivity in 5-FU-resistant CRC cell lines and inhibited the malignant behavior of CRC-resistant cells in vitro. In nude mice with subcutaneous tumors and intraperitoneal injections of 5-FU, tumor tissues formed by BDH2-overexpressing cells exhibited slower growth and increased apoptosis. Mechanistically, the upregulation of BDH2 increases GLIPR1 promoter methylation, mediated by DNA methyltransferases, thereby inhibiting GLIPR1 expression. High expression of GLIPR1 reduces 5-FU sensitivity in 5-FU-resistant CRC cell lines, which abolished the impact of BDH2 expression. These results suggest that BDH2 inhibits GLIPR1 expression by increasing GLIPR1 promoter methylation, thereby enhancing 5-FU sensitivity of 5-FU-resistant CRC cell lines and inhibiting CRC progression.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117153"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636077","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":"Discovery of a potent BRD4 PROTAC and evaluation of its bioactivity in breast cancer cell lines.","authors":"Junjie Hu, Jincui Yang, Runxuan Zhou, Ke Chen, Hongyun Zhao, Yirong Zhou","doi":"10.1016/j.bcp.2025.117159","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117159","url":null,"abstract":"<p><p>Proteolysis targeting chimeras (PROTACs) targeting bromodomain-containing protein 4 (BRD4) proved to be powerful BRD4 degraders, which showed superiority in vitro and in vivo anti-tumor activity in many cancer models. Referring to the design of ARV-825, ARV-771 and MZ1, two novel BRD4 PROTACs were rationally designed and prepared via connecting the pan-BET selective bromodomain inhibitor JQ1 and two universal E3 ligase ligands targeting Von Hippel-Lindau (VHL) and cereblon (CRBN), namely VHL-JQ1 and CRBN-JQ1. Comparable to the degradation potency of ARV-825, ARV-771, and MZ1, both BRD4 PROTACs demonstrated potent BRD4 degradation efficacy. VHL-JQ1 showed superior antitumor activity against triple-negative breast cancer (TNBC) cell lines across multiple cellular processes, including cell proliferation suppression, migration and invasion inhibition, cell cycle arrest, and apoptosis induction. In addition, RNA-seq analysis revealed both shared and distinct gene expression profiles between BRD4 PROTAC-treated and JQ1-treated cells. Notably, VHL-JQ1 induced more pronounced mRNA expression changes compared to CRBN-JQ1 and JQ1. KRAS and NOTCH signaling pathways might be involved in the transcriptomic differences induced by BRD4 PROTACs and JQ1 treatment. Furthermore, combination therapy studies revealed that VHL-Q1 exhibited antagonistic effects when combined with paclitaxel, while demonstrating synergistic effects with cisplatin in TNBC treatment. Overall, our findings highlight VHL-JQ1 as a promising chemical probe for investigating BRD4 biological functions and a potential therapeutic candidate for TNBC treatment.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117159"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636078","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":"Baicalin promotes anti-tumor immunity in hepatocellular carcinoma through HIF-1α/Lactate/CXCL9 axis.","authors":"Xuemei Yang, Weicong Chen, Haitao Sun, Chunyu He, Yang Liu, Mengchen Qin, Wentao Jiang, Yiqin Wang, Songqi He","doi":"10.1016/j.bcp.2025.117157","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117157","url":null,"abstract":"<p><p>Low immune response is a hallmark of several solid tumors, including hepatocellular carcinoma (HCC), highlighting the urgent need for effective immunotherapeutic strategies. Baicalin, a bioactive ingredient derived from traditional Chinese medicine, has exhibited significant anti-tumor activity in various cancer types, yet its effects on anti-tumor immunity remain largely unclear. In this study, we investigated the immunomodulatory role of baicalin in HCC and elucidated its underlying mechanisms. Utilizing a Hepa1-6 subcutaneous tumor model, we observed that baicalin significantly suppressed tumor growth, accompanied by increased CD8⁺ T cell infiltration and elevated secretion of TNF-α and IFN-γ. RNA-sequencing analysis revealed marked enrichment of chemokine pathways, notably with a pronounced upregulation of CXCL9 following baicalin treatment. Importantly, shRNA-mediated knockdown of CXCL9 substantially abrogated baicalin's anti-tumor effects and reduced CD8⁺ T cell infiltration. Integrated metabolomics analysis and lactate inhibition assays further identified lactate as a key regulator of CXCL9 expression. Mechanistically, we demonstrated that HIF-1α, a central regulator of lactate production, is a direct target of baicalin. Baicalin treatment suppressed HIF-1α expression both in vivo and in vitro, corresponding with decreased lactate levels. Conversely, HIF-1α overexpression increased lactate production and inhibited CXCL9 expression. Collectively, our findings reveal that baicalin enhances anti-tumor immunity in HCC through the HIF-1α/lactate/CXCL9 axis, highlighting baicalin as a promising therapeutic candidate for HCC immunotherapy.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117157"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636075","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":"Glimepiride overcomes acquired resistance to EGFR TKIs in lung cancer via the AMPK/ERK/MMP7 signaling pathway.","authors":"Hu Zhang, Min Li, Yan Li, Yi Han, Xin Huang, Ling Li","doi":"10.1016/j.bcp.2025.117162","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117162","url":null,"abstract":"<p><p>Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) limits their clinical efficacy. Intratumoral heterogeneity and the coexistence of diverse resistance mechanisms make combination therapies focused on single molecules or pathways clinically ineffective. Here, our study demonstrated that glimepiride, a sulfonylurea drug, reversed and delayed acquired resistance to EGFR TKIs in lung cancer. Furthermore, glimepiride not only enhanced apoptosis in resistant cells but also suppressed cancer stemness. Mechanistically, glimepiride exerted these effects through AMPK activation, leading to subsequent suppression of the ERK/MMP7 signaling pathway. Our findings identify glimepiride as a promising therapeutic candidate for combination regimens in lung cancer treatment.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117162"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636079","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":"BCAA exaggerated acute and chronic ischemic heart disease through promotion of NLRP3 via Sirt1.","authors":"Yajie Peng, Yusen Duan, Diya Wang, Jingjing Liu, Guangyuan Zhao, Zhangyue Ji, Ji Zhang, Bo Wei","doi":"10.1016/j.bcp.2025.117150","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117150","url":null,"abstract":"<p><p>The study investigated the role and mechanism of branched chain amino acid (BCAA) metabolism in acute myocardial injury and ventricular remodeling post-myocardial infarction. This research employed an integrated approach, combining molecular biology with metabolomics, to investigate the influence of BCAA on acute and chronic myocardial injury both in vivo and in vitro, respectively. In acute myocardial injury, BCAA significantly aggravated acute myocardial injury as demonstrated by remarkably worsen cardiac function and exacerbated biochemical abnormalities, and increased infarct size. Furthermore, BCAA supplementation aggravated the defective metabolism of BCAA by inhibiting the activities of BCAT2, BCKDH and PP2Cm. Interestingly, BCAA dose-dependently promoted pyroptosis in cardiomyocytes via NLRP3/ASC/Caspase-1 activation and cleaved GSDMD in acute myocardial injury. On the other hand, in long-term myocardial infarction (L-MI) induced remodeling, BCAA aggravated the ventricular remodeling in L-MI, and exacerbated the impairment in BCAA metabolism by inhibiting the activities of BCAT2, BCKDH, and PP2Cm. Interestingly, BCAA promoted inflammation in cardiac fibroblasts (CF) in dose-dependently. This process was mediated by inhibiting Sirt1 and enhancing NLRP3 acetylation, thereby activating the NLRP3 inflammasome and promoting CF migration, but without the trigger of pyroptosis. While Knockdown of Sirt1 markedly inhibited NLRP3 activation induced by BCAA in CF. In summary, this study provided a theoretical foundation for developing novel strategies to prevent and treat cardiovascular diseases, and offered valuable guidance for the dietary management of patients with myocardial injury.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117150"},"PeriodicalIF":5.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636076","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}