Biochemical pharmacology最新文献

Dual GPX4/PARP inhibitor YHD-26 exerts potent antitumor activity against triple-negative breast cancer via ferroptosis and DNA damage synergy. 双GPX4/PARP抑制剂YHD-26通过铁下垂和DNA损伤协同作用对三阴性乳腺癌具有有效的抗肿瘤活性。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-09-04 DOI: 10.1016/j.bcp.2026.118433

Honglei Bao, Yupei Lai, Xi Zhao, Weiji Chen, Zixuan Chen, Yaping Guo, Zhendan He, Haiqiang Wu, Dahong Yao

{"title":"Dual GPX4/PARP inhibitor YHD-26 exerts potent antitumor activity against triple-negative breast cancer via ferroptosis and DNA damage synergy.","authors":"Honglei Bao, Yupei Lai, Xi Zhao, Weiji Chen, Zixuan Chen, Yaping Guo, Zhendan He, Haiqiang Wu, Dahong Yao","doi":"10.1016/j.bcp.2026.118433","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118433","url":null,"abstract":"Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, associated with poor prognosis and frequent drug resistance. Ferroptosis refers to an iron-dependent form of non-apoptotic cell death triggered by lipid peroxidation, offering a promising strategy to overcome this resistance. Here, we describe a dual-pharmacophore fusion strategy that hybridizes the electrophilic warhead of a GPX4 inhibitor with the clinical PARP inhibitor niraparib, leading to the design and synthesis of (S)-2-(4-(1-(4-ethynylthiazole-2-carbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (YHD-26), a novel ferroptosis inducer. YHD-26 inhibits PARP (IC50 = 92 nM) and binds GPX4 (KD = 23.4 μM). Mechanistically, YHD-26 exerts potent antiproliferative effects, induces ferroptosis, and impairs DNA damage repair, resulting in G2/M arrest in MDA-MB-468 and 4 T1 cells. In a 4 T1 xenograft mouse model, YHD-26 inhibited GPX4 and PARP, validating its in vivo antitumor efficacy and dual-target engagement. Collectively, YHD-26 represents a novel dual GPX4/PARP inhibitor with therapeutic potential for TNBC.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118433"},"PeriodicalIF":6.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890902","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}

引用次数: 0

Synergistic breakthrough of Melissa officinalis L. Essential oil-loaded nanostructured lipid carrier for combating colistin resistance of MCR-1 positive Escherichia coli. 荷叶沙精油纳米结构脂质载体对抗MCR-1阳性大肠杆菌耐粘菌素的协同突破。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-09-04 DOI: 10.1016/j.bcp.2026.118435

Linlin Ding, Rui He, Yongjia Hu, Jian Liu, Paizati Hamidi, Yerzati Nurman, Lei Xu, Jianfeng Wang, Xuming Deng, Aslebek Zekriya, Ying Chen, Qingjie Li

{"title":"Synergistic breakthrough of Melissa officinalis L. Essential oil-loaded nanostructured lipid carrier for combating colistin resistance of MCR-1 positive Escherichia coli.","authors":"Linlin Ding, Rui He, Yongjia Hu, Jian Liu, Paizati Hamidi, Yerzati Nurman, Lei Xu, Jianfeng Wang, Xuming Deng, Aslebek Zekriya, Ying Chen, Qingjie Li","doi":"10.1016/j.bcp.2026.118435","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118435","url":null,"abstract":"The global spread of multidrug-resistance (MDR) bacteria is devastating health systems and economies worldwide, and this critical trend has revitalized antibiotic adjuvant research. The extensive dissemination of plasmid- or chromosome-mediated resistance genes emphasize the importance of reshaping colistin sensitivity. Here, we report the discovery that Melissa officinalis essential oil isolated from Traditional Chinese medicine, effectively potentiates bactericidal activities of colistin against mobile colistin resistance (MCR-1) positive Escherichia coli (E. coli). Mechanistic analysis demonstrated that Melissa officinalis essential oil interacts with the MCR-1 protein to disrupt LPS modification, while concurrently inducing microbial iron homeostasis disruption and oxidative damage. To enhance its essential oil-mediated therapeutic potential in clinical management, Melissa officinalis essential oil-loaded nanostructured lipid carrier (MOEO-NLC) was designed with improved biocompatibility and solubility. Encouragingly, the combination of MOEO-NLC and colistin achieves bacterial burden reduction and inflammatory response suppression in a peritonitis-sepsis model. Collectively, this study advances antibacterial tactics and underscores the transformative potential of MOEO-NLC in paving the way for enduring countermeasures against antibiotic-resistant threats.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118435"},"PeriodicalIF":6.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890921","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}

引用次数: 0

CRISPR screens for the discovery of novel ferroptosis targets: progress and perspectives. CRISPR筛选发现新的铁下垂靶点：进展和前景。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-09-02 DOI: 10.1016/j.bcp.2026.118410

Weibang Yu, Yiwen Cui, Qi Zhao, Lianxiang Luo

引用次数: 0

Chitosan-selenium nanoparticles prevent retinal ganglion cell apoptosis in glaucoma via activation of the PI3K/Akt/Nrf2 antioxidant axis. 壳聚糖硒纳米颗粒通过激活PI3K/Akt/Nrf2抗氧化轴防止青光眼视网膜神经节细胞凋亡。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-09-02 DOI: 10.1016/j.bcp.2026.118416

Yu-Jia Huo, Miao Wei, Xiao Fan, Li-Wen Peng, Jing-Chang Yuan, Si-Si Tan, Xiao-Chen Wang, Ruo-Tong Ou-Yang, Yi-Jing Zhou, Yan-Yu Pu, Xi Gao, Jun-Qin Lei, Hong Li

{"title":"Chitosan-selenium nanoparticles prevent retinal ganglion cell apoptosis in glaucoma via activation of the PI3K/Akt/Nrf2 antioxidant axis.","authors":"Yu-Jia Huo, Miao Wei, Xiao Fan, Li-Wen Peng, Jing-Chang Yuan, Si-Si Tan, Xiao-Chen Wang, Ruo-Tong Ou-Yang, Yi-Jing Zhou, Yan-Yu Pu, Xi Gao, Jun-Qin Lei, Hong Li","doi":"10.1016/j.bcp.2026.118416","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118416","url":null,"abstract":"Glaucoma is a prominent global cause of irreversible vision loss, fundamentally driven by the continuous degeneration and ultimate death of retinal ganglion cells (RGCs), in which persistent oxidative stress plays a pivotal role. While selenium (Se) offers robust endogenous antioxidant defense, the severe toxicity and narrow therapeutic window of inorganic selenium strictly limit its application. To overcome this critical bottleneck, chitosan-functionalized selenium nanoparticles (CS-SeNPs) are engineered. This strategic nanomodification effectively shields the inherent toxicity of free selenium while conferring improved colloidal stability and biocompatibility. Clinically, systemic Se levels in patients with primary open-angle glaucoma (POAG) are found to be significantly diminished compared to healthy controls. Mechanistically, transcriptome sequencing reveals that CS-SeNPs function through the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway to upregulate the downstream nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant axis, reducing intracellular oxidative stress and apoptosis. In vivo, an intravitreal administration strategy for CS-SeNPs is established. In a rat model of acute ocular hypertension (AOH), this targeted local delivery reduces oxidative damage, preserves retinal hierarchical architecture, and restores visual electrophysiological function. These findings identify systemic Se deficiency as a clinical hallmark of POAG and demonstrate that intravitreal CS-SeNPs offer a promising, intraocular pressure-independent nanotherapeutic strategy for glaucomatous neuroprotection.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118416"},"PeriodicalIF":6.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879138","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}

引用次数: 0

Trimethylamine N-oxide drives cardiac hypertrophy through H3K27ac-mediated enhancer activation of ketohexokinase. 三甲胺n -氧化物通过h3k27ac介导的酮己糖激酶增强子激活驱动心脏肥厚。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-09-02 DOI: 10.1016/j.bcp.2026.118417

Ping Li, Yuan Liu, Gui-Ling Xiong, Hao Wu, Yu-Yan Lei, Yu-Si Wu, Qing Fang, Lu-Lu Chen, Dong-Sheng Ouyang, Jian-Gang Wang, Xiao-Hui Li, Ying Li

{"title":"Trimethylamine N-oxide drives cardiac hypertrophy through H3K27ac-mediated enhancer activation of ketohexokinase.","authors":"Ping Li, Yuan Liu, Gui-Ling Xiong, Hao Wu, Yu-Yan Lei, Yu-Si Wu, Qing Fang, Lu-Lu Chen, Dong-Sheng Ouyang, Jian-Gang Wang, Xiao-Hui Li, Ying Li","doi":"10.1016/j.bcp.2026.118417","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118417","url":null,"abstract":"Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, promotes cardiac hypertrophy, yet the molecular mechanisms linking microbial metabolism to cardiac gene expression remain incompletely defined. Ketohexokinase (KHK), the rate-limiting enzyme of fructose catabolism, is implicated in cardiac pathology, but its role in TMAO-induced hypertrophy is unknown. Here, we show that dietary choline supplementation elevates plasma TMAO and induces pathological cardiac hypertrophy in mice, effects significantly attenuated by the microbial inhibitor 3,3-dimethyl-1-butanol (DMB). RNA sequencing identified Khk as a top upregulated transcript in TMAO-exposed cardiomyocytes, confirmed at the protein level both in vitro and in vivo. Functionally, lentiviral-mediated Khk silencing mitigated hypertrophic growth, mitochondrial dysfunction, and oxidative stress, while pharmacological KHK inhibition with osthole ameliorated cardiac hypertrophy and preserved cardiac function. Mechanistically, TMAO selectively enriched histone H3 lysine 27 acetylation (H3K27ac) at a downstream enhancer of Khk, as revealed by CUT&Tag sequencing and qPCR. Pharmacological blockade of histone acetyltransferase activity with C646 abolished this enhancer activation and KHK upregulation. Targeted motif discovery within the Khk enhancer further identified conserved binding motifs for GATA family transcription factors, which are known to cooperate with p300 to modulate H3K27ac deposition and regulate cardiac hypertrophy genes, suggesting a potential mechanism by which this enhancer may be regulated. Collectively, these findings define a novel TMAO-H3K27ac-KHK axis linking gut microbial metabolism to cardiac remodeling, and identify KHK as a promising druggable target for therapeutic intervention in microbiota-associated heart disease.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118417"},"PeriodicalIF":6.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879157","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}

引用次数: 0

KDM1A/HDAC2-driven epigenetic dysregulation maintains a drug-resistant, relapse-initiating glioblastoma cell niche at the peri-tumoral margin. KDM1A/ hdac2驱动的表观遗传失调维持了肿瘤周围边缘的耐药，引发复发的胶质母细胞瘤细胞生态位。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-09-02 DOI: 10.1016/j.bcp.2026.118415

An-Chih Wu, Jian-Ying Chuang, Jr-Jiun Liu, Enrica Angelina Salim, Ming-Hsiao Wu, Shih-Wei Jing, Tsung-I Hsu, Kwang-Yu Chang, Wen-Chang Chang, Amandeep Thakur, Jing-Ping Liou, Wei-Lun Lo

{"title":"KDM1A/HDAC2-driven epigenetic dysregulation maintains a drug-resistant, relapse-initiating glioblastoma cell niche at the peri-tumoral margin.","authors":"An-Chih Wu, Jian-Ying Chuang, Jr-Jiun Liu, Enrica Angelina Salim, Ming-Hsiao Wu, Shih-Wei Jing, Tsung-I Hsu, Kwang-Yu Chang, Wen-Chang Chang, Amandeep Thakur, Jing-Ping Liou, Wei-Lun Lo","doi":"10.1016/j.bcp.2026.118415","DOIUrl":"10.1016/j.bcp.2026.118415","url":null,"abstract":"Glioblastoma (GBM) is among the most aggressive primary brain tumors, marked by rapid proliferation, therapeutic resistance, and profound intratumoral heterogeneity. Epigenetic regulators such as lysine-specific demethylase 1A (KDM1A) and histone deacetylase 2 (HDAC2) are aberrantly expressed in resistant GBM subpopulations and strongly correlate with poor clinical outcomes. Here, we assessed the therapeutic potential of MPT0G521, a dual KDM1A/class I HDAC inhibitor, in disrupting epigenetic regulation and cell cycle progression. Bioinformatic analyses of resistance-associated gene profiles (temozolomide and 2 Gy radiation) and single-cell transcriptomic datasets from distinct tumor regions revealed enrichment of KDM1A and HDAC2 in high-cycling GBM clusters, particularly at invasive margins prone to recurrence. Functional assays demonstrated that MPT0G521 potently inhibited proliferation of both parental and temozolomide-resistant GBM cells, inducing G2/M arrest and apoptosis. Transcriptomic profiling further identified significant downregulation of centrosome integrity genes (FSD1, KIFC1), spindle regulators (TUBB, STMN1, KIF2C, KIF15), kinetochore components (AURKB, CDCA8, SPAG5), and G2/M checkpoint mediators (CENPF, MYBL2, CCNF, MYT1, CDC25A), resulting in disrupted mitotic progression. Mechanistically, MPT0G521 increased histone H3 methylation and acetylation, validating its dual inhibitory activity against KDM1A and class I HDACs. Collectively, these findings indicate that MPT0G521 disrupts the G2/M activation and mitotic machinery, thereby suppressing proliferative and resistant GBM subpopulations. This dual epigenetic strategy holds strong promise for overcoming GBM heterogeneity and reducing recurrence.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118415"},"PeriodicalIF":6.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879151","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}

引用次数: 0

WTAP-mediated m6A modification upregulates the circCDK8 to promote ferroptosis in periodontal ligament stem cells. wtap介导的m6A修饰上调circCDK8，促进牙周韧带干细胞的铁下垂。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-09-01 DOI: 10.1016/j.bcp.2026.118406

Xu Yang, Peikun Shi

{"title":"WTAP-mediated m6A modification upregulates the circCDK8 to promote ferroptosis in periodontal ligament stem cells.","authors":"Xu Yang, Peikun Shi","doi":"10.1016/j.bcp.2026.118406","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118406","url":null,"abstract":"Impaired osteogenic differentiation of periodontal ligament stem cells (PDLSCs) is a key factor in the failure of alveolar bone repair. Ferroptosis, a form of regulated cell death, has been implicated in osteogenic dysfunction. Wilms' tumor 1-associated protein (WTAP) regulates RNA fate through m6A modification; however, whether WTAP modulates ferroptosis in PDLSCs remains unknown. This study aims to investigate the role of WTAP in LPS-induced ferroptosis in PDLSCs. LPS-treated hPDLSCs were used as cell models. Osteogenic differentiation and inflammation of hPDLSCs, ferroptosis biomarkers, and the expression circular RNA CDK8 (circCDK8), microRNA let-7a-5p (let-7a-5p), transferrin receptor (TFRC), and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) were measured. m6A enrichment on circCDK8 and its binding to Insulin-like Growth Factor 2 mRNA Binding Protein 3 (IGF2BP3) were analyzed. Interactions among circCDK8, let-7a-5p, and TFRC, as well as Y-box Binding Protein 1 (YBX1) recruitment to circCDK8 and ACSL4, were confirmed. Following LPS induction, the expression of WTAP, circCDK8, TFRC, and ACSL4 was upregulated in hPDLSCs, while let-7a-5p expression was downregulated. WTAP knockdown enhanced osteogenic differentiation, reduced inflammation, and decreased ferroptosis in hPDLSCs. Mechanistically, WTAP-mediated m6A modification stabilized circCDK8 through IGF2BP3 binding. CircCDK8 then promoted ferroptosis via two parallel routes: competitively sponging let-7a-5p to upregulate TFRC, and recruiting YBX1 to stimulate ACSL4 expression. Overexpression of circCDK8 or knockdown of let-7a-5p inhibited osteogenic differentiation and promoted ferroptosis. These findings reveal that WTAP drives ferroptosis in PDLSCs through m6A-dependent stabilization of circCDK8, which activates the let-7a-5p/TFRC and YBX1/ACSL4 axes, offering mechanistic insights for alveolar bone repair.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118406"},"PeriodicalIF":6.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872996","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}

引用次数: 0

Corrigendum to "Neutrophil extracellular traps promote glomerular endothelial injury in IgA nephropathy via the cGAS-STING pathway" [Biochem. Pharmacol. 253 (2026) 118354]. “中性粒细胞胞外陷阱通过cGAS-STING途径促进IgA肾病肾小球内皮损伤”[Biochem]的更正。药理学杂志，2004,26(3):118354。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-31 DOI: 10.1016/j.bcp.2026.118391

Xiaotong Li, Qi Duan, Yu Ji, Lu Zhao, Jianbo Qing, Huimin Han, Ru Fan, Yafeng Li

引用次数: 0

Wogonoside: Pharmacology, molecular targets and therapeutic potential. 五味子皂苷：药理、分子靶点和治疗潜力。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-30 DOI: 10.1016/j.bcp.2026.118409

Ming Xie, Jia Liu, Rui Pu, Xiang Qiu, Jiahao Wang, Keyan Zhang, Haibing Hua, Xiandeng Li

{"title":"Wogonoside: Pharmacology, molecular targets and therapeutic potential.","authors":"Ming Xie, Jia Liu, Rui Pu, Xiang Qiu, Jiahao Wang, Keyan Zhang, Haibing Hua, Xiandeng Li","doi":"10.1016/j.bcp.2026.118409","DOIUrl":"10.1016/j.bcp.2026.118409","url":null,"abstract":"Wogonoside, a major flavone 7-O-glucuronide from Scutellaria baicalensis Georgi, has long been used as a quality-control marker for Scutellariae Radix and related traditional herbal formulations. Emerging evidence suggests that wogonoside is not merely an analytical marker or an inactive glucuronide, but a pharmacologically active constituent and potential precursor of bioactive metabolites. In preclinical models, it exhibits anti-inflammatory, antioxidant, anti-angiogenic, anti-fibrotic, antitumor, cardioprotective, neuroprotective, and renoprotective activities. These effects are associated with the regulation of key signaling networks involved in inflammation, oxidative stress, inflammasome activation, autophagy, angiogenesis, fibrosis, and regulated cell death. Representative mechanisms include modulation of TLR4/NF-κB/NLRP3, Nrf2/HO-1, PI3K/AKT/mTOR, AMPK/mTOR, Wnt/β-catenin, Hedgehog/SMO/Gli1, and ferroptosis-related SLC7A11/GPX4 signaling. Recent target-validation studies have identified several candidate molecular targets, including SMO, NF-κB p65, HNF4α, NEK7, GPX4, TLR4, and CD39. However, the strength of evidence varies, and direct target engagement remains to be confirmed for many of these proteins. Pharmacokinetic studies reveal complex disposition characteristics, including intestinal microbial deglycosylation to wogonin, intestinal and hepatic re-glucuronidation, transporter-mediated efflux, enterohepatic or enteric recycling, and frequent multiple-peak plasma profiles. These properties support the value of wogonoside as both a quality-control marker and a dynamic exposure-related marker in Scutellaria-containing preparations. This review summarizes current advances in the chemical analysis, pharmacokinetics, biotransformation, molecular pharmacology, and disease-specific actions of wogonoside, and discusses key challenges for future development, including variable bioavailability, metabolite contribution, target specificity, pharmacokinetic-pharmacodynamic relationships, and clinical translation.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118409"},"PeriodicalIF":6.5,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860445","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}

引用次数: 0

Fetuin-A improves knee osteoarthritis by regulating macrophage PD-1 expression to balance M1/M2 polarization. 胎激素a通过调节巨噬细胞PD-1表达平衡M1/M2极化，改善膝关节骨性关节炎。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-29 DOI: 10.1016/j.bcp.2026.118411

Le Cao, Guohui Liu, Haitao Yang, Wenbin Wu, Ran Zeng

{"title":"Fetuin-A improves knee osteoarthritis by regulating macrophage PD-1 expression to balance M1/M2 polarization.","authors":"Le Cao, Guohui Liu, Haitao Yang, Wenbin Wu, Ran Zeng","doi":"10.1016/j.bcp.2026.118411","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118411","url":null,"abstract":"Knee osteoarthritis (KOA) features cartilage injury, synovial inflammation and abnormal mineralization. Fetuin-A exerts immunomodulatory and anti-mineralization effects, yet its role in KOA remains unclear. This study aimed to clarify whether Fetuin-A alleviates KOA and its underlying mechanism. We established destabilization of the medial meniscus (DMM)-induced KOA mouse models divided into Sham, Model, Fetuin-A, and Fetuin-A+anti-programmed cell death protein 1 (PD-1) groups. LPS-stimulated bone marrow-derived macrophage conditioned medium (BMDM-CM) system was constructed, with BMDMs grouped into Control, Model, Fetuin-A, and Fetuin-A+small interfering RNA targeting PD-1 (si-PD-1). Primary chondrocytes were incubated with corresponding CM, and we adopted micro-computed tomography, X-ray, histopathology, flow cytometry, Western blotting, ELISA and qPCR to detect joint lesions, macrophage polarization, inflammation and mineralization markers. In vivo tests showed reduced Fetuin-A in serum and synovial fluid of KOA mice, accompanied by joint stenosis, cartilage damage, M1 macrophage polarization and decreased PD-1. Fetuin-A supplementation reversed these pathological changes, while PD-1 blockade eliminated such protective effects. In vitro assays verified that Fetuin-A upregulated macrophage PD-1 to suppress M1 polarization, boost M2 polarization and lower interleukin-1β and tumor necrosis factor-α secretion. Fetuin-A-treated macrophage CM relieved chondrocyte injury, apoptosis, matrix degradation and abnormal mineralization, which was abolished by PD-1 knockdown. In summary, Fetuin-A balances M1/M2 polarization via elevating macrophage PD-1 expression, thus mitigating cartilage damage, synovitis and abnormal mineralization in KOA.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118411"},"PeriodicalIF":6.5,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856949","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}

引用次数: 0