Biochemical pharmacology最新文献

{"title":"Comprehensive non-small cell lung cancer targets: From computational prediction to clinical breakthroughs in overcoming drug resistance","authors":"Wanjie Zheng ,&nbsp;Zhiheng He ,&nbsp;Jiarui Liu ,&nbsp;Yuting Zhang ,&nbsp;Chengjun Gong ,&nbsp;Baojie Wang ,&nbsp;Jie Shen ,&nbsp;Li Guo ,&nbsp;Tingming Liang","doi":"10.1016/j.bcp.2025.117333","DOIUrl":"10.1016/j.bcp.2025.117333","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC), the predominant subtype of lung cancer, remains a leading contributor to global cancer-related mortality. Conventional treatments—surgery, chemotherapy, and radiotherapy—are often limited by suboptimal efficacy and substantial toxicity, underscoring the urgent need for more effective targeted therapies. This study provides a comprehensive overview of three key advancements in NSCLC research. First, it highlights state-of-the-art target prediction methodologies that integrate ligand-based, structure-based, and multi-feature deep learning models, supported by experimental validation. Second, it examines clinical progress in targeting classical oncogenic drivers, exemplified by the fourth-generation tyrosine kinase inhibitor amivantamab against epidermal growth factor receptor (EGFR), and explores mechanisms of drug resistance, such as T790M and C797S mutations, along with emerging strategies like synthetic lethality-based interventions. Third, it discusses combination regimens—such as osimertinib co-administered with savolitinib—that mitigate resistance by synergistically inhibiting compensatory signaling pathways, thereby enhancing clinical outcomes. Future research priorities include the design of multi-target therapeutics and the refinement of AI-driven target discovery frameworks. This review addresses current limitations in targeted NSCLC therapy and offers insights to guide future therapeutic development.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117333"},"PeriodicalIF":5.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063416","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":"Recombinant AAV gene transfer: Emerging applications in immune modulation and cancer therapy","authors":"Yixuan Yang ,&nbsp;Rongtao Chen ,&nbsp;Yuchen Bao ,&nbsp;Heqiao Han ,&nbsp;Kai Ma ,&nbsp;Xiaolei Pei ,&nbsp;Lei Zhang ,&nbsp;Wenwei Shao","doi":"10.1016/j.bcp.2025.117332","DOIUrl":"10.1016/j.bcp.2025.117332","url":null,"abstract":"<div><div>Advancements have been achieved in gene transfer using recombinant adeno-associated virus (rAAV). rAAVs with distinct tissue tropisms are used to deliver target genes safely and accurately to specific host tissue. Although primarily used for treating monogenic disease, rAAV vectors also have potential in the field of immune modulation. Gene delivery through rAAV vectors, particularly those encoding immune regulatory molecules, not only mitigates inflammation and corrects immune dysfunction but also suppresses tumor growth and enhances the efficacy of Chimeric Antigen Receptor T cell therapy via immune modulation, thereby exerting anti-cancer effects. rAAV-based immune therapies primarily focus on autoimmune diseases, including rheumatoid arthritis, autoimmune uveitis, multiple sclerosis and other genetic immune diseases but may also be used to treat hepatocellular carcinoma, glioma and ovarian cancer. The present review aims to outline the advantages and limitations of rAAV gene delivery vectors and their potential applications in immune therapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117332"},"PeriodicalIF":5.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063428","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":"NUCKS1, a gene targeted by miR-497-5p, suppresses the antitumor effect of Brusatol and enhances malignancy of HNSCC via upregulating S100A9 expression","authors":"Changhong Ma ,&nbsp;Jiajun Song ,&nbsp;Haipeng Feng ,&nbsp;Xintong Kui ,&nbsp;Sha Liu ,&nbsp;Shuhan Shi ,&nbsp;Xiaojie Li ,&nbsp;Linghao Tang","doi":"10.1016/j.bcp.2025.117328","DOIUrl":"10.1016/j.bcp.2025.117328","url":null,"abstract":"<div><div>Brusatol (Bru), an extract derived from the Chinese medicinal plant Brucea javanica, exhibits a variety of antitumor effects. However, the precise role and regulatory mechanisms of Brusatol in head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we demonstrated that Brusatol promotes HNSCC cell death and inhibits cell growth and tumorigenesis both in vitro and in vivo. Mechanistically, Brusatol reduces the expression of Nuclear Ubiquitous Casein and Cyclin-Dependent Kinase Substrate 1 (NUCKS1). Elevated levels of NUCKS1 suppress Brusatol-induced cell death, whereas depletion of NUCKS1 enhances the antitumor effects of Brusatol. Additionally, NUCKS1 is significantly upregulated in HNSCC tissues, and its inhibition markedly reduces cell growth and tumorigenesis. Further investigations revealed that NUCKS1 ablation decreases the expression of S100 Calcium-Binding Protein A9 (S100A9). NUCKS1 enhances the activity of the S100A9 promoter and facilitates its transcription. Furthermore, our data indicate that miR-497-5p is upregulated in response to Brusatol treatment, which subsequently binds to the 3′UTR of NUCKS1 and downregulates its expression in HNSCC. Collectively, these findings highlight the critical role and regulatory mechanisms of NUCKS1 in HNSCC, suggesting that NUCKS1 antagonizes the antitumor effects of Brusatol and exacerbates the malignancy of HNSCC cells via transcriptional upregulation of S100A9.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117328"},"PeriodicalIF":5.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044155","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 TDP-43-activated GRP78/endoplasmic reticulum stress axis suppresses triple-negative breast cancer progression","authors":"Jiao Wang ,&nbsp;Haotian Xu ,&nbsp;Li Tang","doi":"10.1016/j.bcp.2025.117331","DOIUrl":"10.1016/j.bcp.2025.117331","url":null,"abstract":"<div><div>The TAR DNA-binding protein-43 (TDP-43), a highly conserved DNA/RNA binding protein encoded by the TARDBP gene, has garnered extensive scientific attention in the realm of neurodegenerative diseases. Notably, its association with malignant tumors has become increasingly apparent in recent years. This investigation aims to examine the role of TDP-43 in triple-negative breast cancer (TNBC) and to clarify the underlying mechanisms. Bioinformatics analysis showed that TDP-43 was substantially up-regulated in breast cancer tissues. Elevated TDP-43 expression stimulated TNBC cell proliferation and migration in vitro, and accelerated tumor progression in vivo. TDP-43 was identified as a promoter of tumor growth, with its inhibition resulting in a significant impediment to cell growth. Additionally, the overexpression of Glucose-regulated protein 78 (GRP78) counteracted the suppressive effect on cell proliferation and migration observed upon TDP-43 knockdown, affirming TDP-43′s critical role in breast cancer cell proliferation and migration. Mechanistic investigations have demonstrated that TDP-43 binds directly to GRP78 mRNA, stimulating its expression. The up-regulation of GRP78, a master regulator of the unfolded protein response, activates the inositol-requiring enzyme 1 alpha (IRE1α) pathway, exacerbating endoplasmic reticulum (ER) stress. Consequently, this process enhances the proliferation and migration of TNBC cells, contributing significantly to tumor progression. Here, we demonstrate that TDP-43 promotes cell proliferation and migration by regulating ER stress in breast cancer, offering valuable insights into the mechanistic intricacies of TDP-43 in TNBC and holding potential implications for precision treatments in this context.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117331"},"PeriodicalIF":5.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063555","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":"KDM5C: A dual-edged epigenetic regulator in cancer biology-context-dependent roles and therapeutic implications","authors":"Fei-Yang Tu ,&nbsp;Yan-Jun Liu ,&nbsp;Xiang Li ,&nbsp;Ke-Fan Cao ,&nbsp;Jing Yu ,&nbsp;Ran Wang ,&nbsp;Guan–Jun Yang ,&nbsp;Jiong Chen","doi":"10.1016/j.bcp.2025.117327","DOIUrl":"10.1016/j.bcp.2025.117327","url":null,"abstract":"<div><div>Lysine-specific demethylase 5C (KDM5C is a histone demethylase that) serves as a critical epigenetic regulator of H3K4 methylation, with context-dependent roles in cancer progression. While functioning as a tumor suppressor in clear-cell renal cell carcinoma (ccRCC) by maintaining genomic stability and inhibiting HIF signaling, it acts as an oncogenic driver in prostate, breast, and hepatocellular carcinomas by promoting epithelial–mesenchymal transition (EMT), metabolic reprogramming, and chemoresistance. KDM5C orchestrates these opposing functions via interactions with key regulators (ARX, Smad3, and HIF1α) and remodeling of chromatin landscapes to enhance tumor plasticity. Its clinical significance is underscored by therapeutic resistance mechanisms, including CD44 cooperation in pancreatic cancer and HPV E6-mediated lncRNA activation in cervical cancer. Although preclinical studies demonstrate that KDM5C inhibitors can overcome drug tolerance and suppress tumorigenesis, challenges persist in achieving subtype specificity and reducing off-target effects. Beyond oncology, KDM5C dysregulation contributes to Claes-Jensen syndrome and neurodevelopmental disorders, reflecting its pleiotropic functions. Future directions should integrate single-cell omics and targeted inhibitor development to elucidate microenvironmental interactions and enable precision therapies. This synthesis positions KDM5C as a pivotal epigenetic nexus in disease pathogenesis, offering context-dependent therapeutic opportunities.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117327"},"PeriodicalIF":5.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058253","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":"Bavachinin exerts anti-tumor effects by activating TLR4/STING axis-dependent PANoptosis and synergistically enhances chemosensitivity in endometrial cancer","authors":"Wan Shu ,&nbsp;Guanxiao Chen ,&nbsp;Jun Zhang,&nbsp;Kejun Dong,&nbsp;Ting Zhou,&nbsp;Shuangshuang Cheng,&nbsp;Tangansu Zhang,&nbsp;Jiarui Zhang,&nbsp;Haojia Li,&nbsp;Yuwei Yao,&nbsp;Shuyang Yu,&nbsp;Yan Liu,&nbsp;Xing Zhou,&nbsp;Xiaoyu Shen,&nbsp;Hongbo Wang","doi":"10.1016/j.bcp.2025.117321","DOIUrl":"10.1016/j.bcp.2025.117321","url":null,"abstract":"<div><div>The incidence and mortality rates of endometrial cancer (EC), a malignancy originating from endometrium, have been increasing globally. Currently, there are no effective therapeutic options for patients with recurrent, chemoresistant, and metastatic forms of this disease. Through compound library screening, we identified that bavachinin (BVC) has a killing effect on EC cells. BVC is a bioactive small molecule with potential pharmacological effects derived from the traditional Chinese herb <em>Proralea corylifolia L</em>, but the specific mechanisms are unclear. We first discovered that BVC induces ZBP1 (Z-DNA binding protein 1)-mediated PANoptosis in EC cells, characterized by activating of pyroptosis, apoptosis, and necroptosis. BVC promoted reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP, ΔΨm) collapse, and ATM-CHK2 mediated DNA damage, which activated cGAS-STING pathway in EC cells. Mechanistically, network pharmacology, molecular docking, cellular thermal shift assays (CESTA), and drug affinity responsive target stability (DARTS) experiments revealed that BVC induced PANoptosis in EC cells by directly interacting with toll-like receptor 4 (TLR4), thereby triggering mitochondrial ROS generation, activating the cGAS-STING pathway. Notably, TLR4 knockdown inhibited STING-TBK1-IRF3 pathway and ZBP1-mediated PANoptosis. In addition, low-dose BVC combined with cisplatin increased phosphorylated H2AX expression, suggesting that BVC enhances the sensitivity of EC cells to cisplatin. In vivo studies demonstrated that BVC induced PANoptosis in EC, and BVC in combination with cisplatin had effective anti-tumor effect without injuring vital organs. These novel findings provide compelling evidence to support the clinical application of BVC and PANoptosis-based therapy for treating EC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117321"},"PeriodicalIF":5.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051710","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":"TEA domain transcription factor 3 suppresses aortic and left ventricular remodeling via transcriptional activation of PDZ domain containing 1","authors":"Lei Wang ,&nbsp;Yufeng Bai ,&nbsp;Dan Ma ,&nbsp;Wenxiu Liu ,&nbsp;Zhiyu Shi ,&nbsp;Chunnan Liu ,&nbsp;Meng Zhao ,&nbsp;Huiying Wang ,&nbsp;Liying Luo ,&nbsp;Jinyu Chi","doi":"10.1016/j.bcp.2025.117329","DOIUrl":"10.1016/j.bcp.2025.117329","url":null,"abstract":"<div><div>Hypertension is a risk factor for cardiovascular diseases, primarily through its induction of pathological vascular and ventricular remodeling. TEA domain transcription factor 3 (TEAD3) is a transcription factor highly expressed in myocardial tissues. PDZ domain-containing 1 (PDZK1) has been reported to protect blood vessels. This study discovered decreased expression of TEAD3 and PDZK1 in the aortic tissues of spontaneously hypertensive rats (SHRs). TEAD3 overexpression in SHR vascular smooth muscle cells (VSMCs) driven by the SM22α promoter was achieved through adeno-associated virus delivery. TEAD3 overexpression alleviated aortic remodeling by reducing elastic fiber and collagen deposition. This improvement in vascular structure attenuated hypertension. Subsequently, ventricular remodeling was alleviated by reducing periaortic myocardial fibrosis and left ventricular posterior wall thickness. To elucidate the underlying mechanisms, we overexpressed TEAD3 or PDZK1 in SHR-derived VSMCs via adenoviral infection. Both interventions suppressed VSMC proliferation and migration. Crucially, TEAD3 overexpression upregulated PDZK1 expression, and DNA pull-down assays confirmed direct binding of TEAD3 protein to the PDZK1 promoter. PDZK1 knockdown abolished the anti-proliferative and anti-migratory effects of TEAD3. Further analysis suggested that PDZK1 exerted its protective role by inhibiting the phosphoinositide-3-kinase adaptor protein 1-mediated PI3K/Akt pathway. In conclusion, this study reveals that TEAD3-PDZK1 axis attenuates the abnormal proliferation and migration of VSMCs, which ameliorates aortic and left ventricular remodeling in hypertensive conditions. These findings establish a molecular basis for developing targeted therapies against hypertension-induced cardiovascular remodeling.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117329"},"PeriodicalIF":5.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051718","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":"Epigenetic regulation of extracellular matrix mechanotransduction in cardiac fibrosis","authors":"Li-Chan Lin ,&nbsp;Zhen-Yu Liu ,&nbsp;Sui Mao ,&nbsp;Peng Liu ,&nbsp;Jing-Jing Yang ,&nbsp;Jian-Yuan Zhao ,&nbsp;Hui Tao","doi":"10.1016/j.bcp.2025.117325","DOIUrl":"10.1016/j.bcp.2025.117325","url":null,"abstract":"<div><div>Cardiac fibroblasts activation and cardiac fibrosis is a pathophysiological repair process that respond to various detrimental stimuli in the heart, leading to reduced ventricular diastolic compliance, impaired mechanotransduction, drastic changes in heart rhythm and pumping function, and obstruction of gas-blood exchange. To some extent, these changes are reflected in the cardiac mechanotransduction remodeling, as well as changes in the quantity, composition, and hardness of extracellular matrix, hemodynamic forces, mechanosensitive signal transduction, and epigenetic regulation related to cardiac mechanics. Cardiac fibroblasts biosynthesize and secrete extracellular matrix, and even receive signals from extracellular matrix<!--> <!-->through many different surface receptors and complexes, which are important for mechanotransduction. Besides, the mechanical properties of the microenvironment are critical for ascertaining fibrotic responses and cardiac performance. This review provides an overview of the multiscale mechanics changes in the heart and details how the mechanical molecular factors influence cardiac mechanotransduction and fibrosis development. Finally, we discuss and consider how mechanically targeted agents affect these mechanotransduction events in the heart, hoping to provide insights for the future treatment of corresponding human pressure overload-induced cardiac fibrosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117325"},"PeriodicalIF":5.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051692","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":"Evodiamine induces centrosome amplification with subsequent G2/M cell cycle arrest in primary vascular smooth muscle cells","authors":"Patricia Haiss ,&nbsp;Rongxia Liu ,&nbsp;Feng Xian ,&nbsp;David Gomez Varela ,&nbsp;Manuela Schmidt ,&nbsp;Verena M. Dirsch ,&nbsp;Tina Blažević","doi":"10.1016/j.bcp.2025.117320","DOIUrl":"10.1016/j.bcp.2025.117320","url":null,"abstract":"<div><div>Evodiamine (EVO) is a natural product found in <em>Tetradium ruticarpum</em>. It inhibits vascular smooth muscle cell (VSMC) proliferation, a key mechanism in the pathogenesis of atherosclerosis and restenosis. This study characterizes the mechanism of action behind the antiproliferative activity of evodiamine in platelet derived growth factor (PDGF)-activated VSMC.</div><div>We confirmed the antiproliferative activity of EVO (0.3 and 1 µmol/L) in cultured primary VSMC by resazurin conversion and bromo-deoxyuridine (BrdU) incorporation assays, respectively, and its ability to arrest VSMC in G2/M by flow cytometric cell cycle analysis. Annexin V- Fluorescein Isothiocyanate (FITC)/propidium iodide (PI) staining and western blot analysis of caspase-3 cleavage detected low levels of apoptosis in response to 3 µmol/L EVO. We demonstrate that EVO (3 µmol/L) induces mitotic catastrophe (MC), as evidenced by characteristic nuclear morphology observed by confocal microscopy and polyploidy detected by flow cytometric DNA content analysis.</div><div>Mechanistically, we rule out DNA damage as a cause of MC by western blot analysis of phospho-Ser139 histone H2A.X (γH2A.X). Instead, EVO induces centrosome amplification involving polo-like kinase 4 (PLK4) signaling. This is evident in cells co-treated with EVO (3 µmol/L) and the PLK4 inhibitor centrinone B (CENB) at 125 nmol/L by blunted centrosome amplification and cell cycle arrest. The study concludes with a proteomic analysis of purified centrosomes, which identifies candidates involved in this mechanism.</div><div>In conclusion, evodiamine induces mitotic catastrophe via centrosome amplification in VSMC, positioning it as an antiproliferative agent with a distinct mechanism.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117320"},"PeriodicalIF":5.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038996","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":"REG3A promotes gemcitabine resistance in pancreatic cancer via the GPR54/ARRB2/ERK1/2 ligand-directed signaling pathway","authors":"Jia Liu ,&nbsp;Senlin Li ,&nbsp;Hong Zhou ,&nbsp;Mengheng Wang ,&nbsp;Chengliang Zhang ,&nbsp;Cheng Tian ,&nbsp;Yue Xu ,&nbsp;Mengxuan Wang ,&nbsp;Xin Li ,&nbsp;Qing Li ,&nbsp;Ming Xiang","doi":"10.1016/j.bcp.2025.117322","DOIUrl":"10.1016/j.bcp.2025.117322","url":null,"abstract":"<div><div>Gemcitabine is a widely employed first-line chemotherapeutic drug for pancreatic cancer (PCa). However, the rapid emergence of gemcitabine resistance poses a major clinical hurdle. Here, we identified REG3A as a crucial determinant of poor prognosis in PCa. Notably, REG3A was upregulated in tumor tissues from clinical gemcitabine-resistant PCa patients. Through comprehensive in vitro cellular assays and in vivo studies using Reg3g (the murine homolog of REG3A) knockout mice, we demonstrated that REG3A deficiency sensitized PCa to gemcitabine treatment. Mechanistically, RNA sequencing (RNA-Seq) combined with Protein-Protein Interaction (PPI) analysis revealed that REG3A functioned as an exocytosis protein binds to the novel membrane receptor GPR54. The interaction increased membrane localization of GPR54, which subsequently engaged ARRB2 as a scaffolding molecule, leading to activation of the ERK1/2 pathway and suppression of gemcitabine-induced apoptosis. Moreover, the GPR54 agonist KP10 synergistically enhanced gemcitabine resistance in conjunction with REG3A, while interference with GPR54 or its antagonist KP234 attenuated REG3A-induced gemcitabine resistance. Targeting REG3A or pharmacologically inhibiting its downstream signaling molecules may represent a promising strategy to overcome gemcitabine resistance. Overall, REG3A could serve as a potential biomarker for gemcitabine resistance in PCa, offering a new avenue for therapeutic intervention and patient stratification.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117322"},"PeriodicalIF":5.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038998","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}