Biochemical pharmacology最新文献

{"title":"Precision vaccine design targeting the prefusion state of viral glycoproteins: advances in structural vaccinology","authors":"Reetesh Kumar ,&nbsp;Somnath Maji ,&nbsp;Savitri Tiwari ,&nbsp;Jyotsna Misra ,&nbsp;Jyoti Gupta ,&nbsp;Naveen Kumar ,&nbsp;Rohan Gupta ,&nbsp;Niraj Kumar Jha","doi":"10.1016/j.bcp.2025.117349","DOIUrl":"10.1016/j.bcp.2025.117349","url":null,"abstract":"<div><div>The prefusion conformation of viral glycoproteins is a key target for vaccine development because it can induce strong neutralizing antibody responses. Nevertheless, these structures are frequently metastable and susceptible to conformational alterations that diminish immunogenic efficacy. Progress in structural vaccinology has facilitated the meticulous design of viral proteins to maintain their prefusion conformation, thus improving vaccination effectiveness. This study emphasizes essential methodologies in precision vaccine design focused on preserving the structural integrity, solubility, and immunogenicity of viral glycoproteins. Methods include cavity-filling mutations, proline insertions, and disulfide bond engineering have demonstrated efficacy in enhancing structural stiffness and inhibiting unwanted post-fusion rearrangements. Hydrophobic surface residues are frequently substituted with polar or charged residues to boost solubility and minimize aggregation, while the development of salt bridges and helix-stabilizing substitutions further augment heat stability. The removal of proteolytic cleavage sites and the enhancement of hydrophobic core packing facilitate sustained conformational integrity. Alterations to the fusion peptide, an essential conserved area for viral entry, can inhibit early conformational changes, whereas charge-balancing alterations mitigate electrostatic stress. Glycan shielding conceals non-neutralizing or immunodominant epitopes, steering immune reactions towards conserved, protective areas. Collectively, these structure-guided interventions constitute a thorough molecular toolset, facilitating the creation of prefusion-stabilized immunogens for advanced vaccines. Successfully implemented in vaccine candidates for Respiratory Syncytial Virus (RSV), Human Immunodeficiency Virus (HIV), and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), these methodologies establish a solid basis for the swift and logical generation of vaccines against emerging viral threats.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117349"},"PeriodicalIF":5.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091136","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":"Circadian rhythm disturbance induces osteoarthritis in mice: Involvement of Clock and Bmal1 dysregulation and Pdgfa inhibition","authors":"Ao Guo ,&nbsp;Ke Zheng ,&nbsp;Wanqi Jia ,&nbsp;Shengting Zhang ,&nbsp;Cong Sui","doi":"10.1016/j.bcp.2025.117342","DOIUrl":"10.1016/j.bcp.2025.117342","url":null,"abstract":"<div><div>Circadian rhythm disturbance (CRD) is likely associated with impaired bone development and the development of osteoarthritis (OA). This study investigates the functions of circadian locomotor output cycles kaput (<em>Clock</em>) and brain and muscle Arnt-like 1 (<em>Bmal1</em>) in OA progression and explores the implicated molecular mechanisms. Mice were subjected to CRD for 70 d. This led to significant OA-like symptoms, accompanied by a reduction in the expression of <em>Clock</em> and <em>Bmal1</em>. Either <em>Clock</em> or <em>Bmal1</em> upregulation reduced serum concentrations of inflammatory cytokines (interleukin [IL]-1β and IL-6) in mice, and it reduced cartilage erosion and extracellular matrix degradation in their knee joints, with parallel findings observed in the isolated chondrocytes <em>in vitro</em>. The Clock:Bmal1 heterodimer binds to the enhancer upstream of the <em>Pdgfa</em> promoter to enhance its transcription. <em>Pdgfa</em> knockdown reversed the protective effects of <em>Clock</em> and <em>Bmal1</em> by inactivating the Pi3k/Akt and Erk1/2 cascade. By contrast, <em>Pdgfa</em> overexpression reduced chondrocyte damage, which was, however, negated by the Pi3k/Akt inhibitor LY294002. Collectively, this study validates that CRD is pertinent to the development of OA. Restoring <em>Clock</em> and <em>Bmal1</em> levels may help ameliorate chondrocyte loss in CRD-associated OA by activating <em>Pdgfa</em> transcription and enhancing Pi3k/Akt and Erk1/2 signaling pathways.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117342"},"PeriodicalIF":5.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091131","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":"Coffee for the liver: a mechanistic approach","authors":"Eduardo E. Vargas-Pozada ,&nbsp;Erika Ramos-Tovar ,&nbsp;Linda Vanessa Márquez-Quiroga ,&nbsp;Karla Jocelyn Ortega-Carballo ,&nbsp;Pablo Muriel","doi":"10.1016/j.bcp.2025.117338","DOIUrl":"10.1016/j.bcp.2025.117338","url":null,"abstract":"<div><div>The liver, which is essential for metabolism and detoxification, is vulnerable to various damaging factors, including viral infections, excessive alcohol consumption, and a diet high in fat and sugar. Coffee, one of the most widely consumed beverages worldwide, is valued not only for its flavor and aroma but also for its potential health benefits. In this context, the protective effects of its consumption against liver diseases have been extensively studied. Epidemiological, experimental, and clinical evidence suggests that regular coffee consumption reduces the risk of liver disease and slows its progression to fibrosis, cirrhosis, and hepatocellular carcinoma. These benefits are attributed to its complex composition comprising various bioactive compounds such as caffeine, polyphenols, and diterpenes, which have anti-inflammatory, antioxidant, antifibrotic, and anticancer properties. Coffee mitigates liver damage and slows disease progression by modulating cellular responses, reducing oxidative stress, and restoring metabolic homeostasis. Several studies have demonstrated that coffee and its bioactive compounds regulate key pathways involved in inflammation, oxidative stress, and fibrosis while modulating hepatic lipid metabolism and insulin resistance. Furthermore, coffee can alter the composition of the gut microbiota, contributing to its hepatoprotective effects. Additionally, coffee consumption has been associated with lower liver enzyme levels, less liver structural damage in patients with various liver diseases, and reduced liver disease-related mortality. This narrative review explores the impact of coffee consumption on liver health and discusses epidemiological evidence, cellular and molecular mechanisms, and clinical implications for the prevention, treatment, and management of liver diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117338"},"PeriodicalIF":5.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079578","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":"Myokine-mediated muscle-organ interactions: Molecular mechanisms and clinical significance","authors":"Jia Yi ,&nbsp;Junyang Chen ,&nbsp;Xinlei Yao ,&nbsp;Zihao Zhao ,&nbsp;Xinxin Niu ,&nbsp;Xia Li ,&nbsp;Jiacheng Sun ,&nbsp;Yanan Ji ,&nbsp;Tongxin Shang ,&nbsp;Leilei Gong ,&nbsp;Bingqian Chen ,&nbsp;Hualin Sun","doi":"10.1016/j.bcp.2025.117326","DOIUrl":"10.1016/j.bcp.2025.117326","url":null,"abstract":"<div><div>Regular exercise training preserves systemic homeostasis via coordinated multi-organ interactions, with skeletal muscle emerging as a pivotal effector organ and integrative signaling nexus. Recent breakthroughs in research have established the endocrine organ properties of skeletal muscle. Through contraction-induced release of myokines, skeletal muscle employs multimodal signaling mechanisms including autocrine, paracrine, and endocrine pathways, systematically elucidating the molecular basis of exercise benefits. This review innovatively proposes the “Myokine-mediated Multi-organ Metabolic Network” theory, comprehensively summarizing the role of myokines in mediating inter-organ crosstalk and dynamic communication mechanisms. These interactions involve skeletal muscle itself and multiple vital organs including heart, liver, lung, kidney, pancreas, brain, bone, skin, oral cavity, adipose tissue, intestine, stomach, mammary glands, ovaries, and prostate. Mechanistic insights elucidate that myokines function as pleiotropic signaling modulators, orchestrating multifaceted regulatory programs across six interconnected biological axes, including energy substrate flux and mitochondrial biogenesis, osteogenic differentiation and extracellular matrix remodeling, neuroplasticity and Blood-brain barrier (BBB) homeostasis, gut microbiota modulation, vascular endothelial function, and immunometabolic reprogramming within neoplastic niches. Notably, the multi-target regulatory capacity of myokines provides mechanistic insights into exercise-induced disease resistance. As “exercise-mimetic molecules,” targeted delivery strategies of myokines provide novel therapeutic directions for metabolic diseases, neurodegenerative disorders, and cancer treatment. Crucially, three research frontiers demand prioritization: decoding spatiotemporal myokine secretion patterns; mapping receptor-ligand interaction networks across organs; and developing computational models predicting system-level responses to myokine modulation. Addressing these challenges will catalyze the translation of exercise physiology discoveries into precision therapeutics.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117326"},"PeriodicalIF":5.6,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074421","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":"Activation of the Nrf2/HO-1/GPX4 pathway by cGAMP Mitigates oxidative stress and ferroptosis in ischaemic stroke","authors":"Xinyu Li ,&nbsp;Shuyu Qian ,&nbsp;Zhiqi Hou ,&nbsp;Guoling Yang ,&nbsp;Yulin Ma ,&nbsp;Yuan Gao ,&nbsp;Yuefan Zhang ,&nbsp;Tiejun Li","doi":"10.1016/j.bcp.2025.117334","DOIUrl":"10.1016/j.bcp.2025.117334","url":null,"abstract":"<div><div>Ischemic stroke(IS), a leading cause of neurological disability worldwide, involves intricate crosstalk between oxidative stress and regulated cell death pathways. In this study, we demonstrate that the immunomodulatory metabolite 2′3′-cyclic GMP-AMP (cGAMP) exerts neuroprotective effects using a mouse model of transient focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO), significantly decreased brain lesion size with concurrent amelioration of neurobehavioral outcomes through mechanisms distinct from canonical cGAS-STING signaling. cGAMP-dependent activation of the Nrf2/HO-1/GPX4 pathway was identified by multimodal interrogation as the primary mechanism curbing mitochondrial oxidative stress and lipid peroxidation, accompanied by ultrastructural preservation of mitochondrial cristae integrity and a reduction in ferroptotic markers. Pharmacological inhibition of Nrf2 using ML-385 or GPX4 with ML-210 completely abrogated these protective effects, thereby confirming pathway specificity. These findings establish cGAMP as a novel dual modulator of redox homeostasis and ferroptosis in ischemic stroke pathophysiology.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117334"},"PeriodicalIF":5.6,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074411","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":"HSP90-specific inhibitor, PSY-2–12, ameliorates cellular senescence via activating autophagy: A potential senotherapeutic target against acute kidney injury","authors":"Thuy Quynh Nhu Nguyen ,&nbsp;Ai-Han Nguyen ,&nbsp;Manh Quoc Dao ,&nbsp;Mikyung Kim ,&nbsp;Thi Tuyet Mai Pham ,&nbsp;Seojin Kim ,&nbsp;Ji Hae Seo ,&nbsp;Young Ho Seo ,&nbsp;Eunyoung Ha","doi":"10.1016/j.bcp.2025.117336","DOIUrl":"10.1016/j.bcp.2025.117336","url":null,"abstract":"<div><div>An unexpected senotherapeutic function of heat shock protein 90 (HSP90) inhibitors—drugs long developed as cancer therapeutics—has recently been revealed. In this study, we employed an HSP90-specific inhibitor, PSY-2–12 (PSY), to explore its potential therapeutic application as a senomorphic agent. We demonstrated that PSY, at non-toxic concentrations, reduces cellular senescence in both cisplatin (CP)-induced senescent kidney proximal tubular cells and angiotensin II-induced senescent human umbilical vein endothelial cells. The anti-senescent effect of PSY was further confirmed in a mouse model of CP-induced acute kidney injury (AKI). PSY treatment attenuated CP-induced kidney injury, as evidenced by decreased levels of urea, creatinine, and kidney injury molecule-1, and ameliorated CP-induced senescence, as shown by reduced β-galactosidase staining and p16 expression, along with increased lamin B1 levels compared with controls. Mechanistically, we found that PSY exerts its senotherapeutic effects through beclin-1–mediated stimulation of autophagy. PSY enhanced beclin-1 expression and autophagic flux in CP-treated proximal tubular cells, while inhibition of autophagy reversed the senotherapeutic effects of PSY. Similarly, beclin-1 knockdown abolished the protective effects. In summary, our results suggest that PSY, an HSP90-specific inhibitor, may serve as a promising senomorphic therapeutic agent for the treatment of AKI.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117336"},"PeriodicalIF":5.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069042","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":"The regulatory roles of pparα on hepatic drug-metabolizing enzymes in primary sclerosing cholangitis Syrian hamsters","authors":"Shuaibing Liu ,&nbsp;Jinxin Miao ,&nbsp;Hang Li ,&nbsp;Guangbo Ge ,&nbsp;Quanjun Yang ,&nbsp;Songfeng Zhao ,&nbsp;Cheng Guo","doi":"10.1016/j.bcp.2025.117339","DOIUrl":"10.1016/j.bcp.2025.117339","url":null,"abstract":"<div><div>Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, ultimately leading to liver dysfunction. The role of peroxisome proliferator-activated receptor α (pparα) in regulating hepatic drug-metabolizing enzymes, including cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs), in PSC remains insufficiently understood. In this study, wild-type and pparα −/− Syrian hamsters were used to establish a PSC model, aiming to investigate the effects of pparα on the expression and activity of P450 and UGT enzymes. Sequential windowed acquisition of all theoretical fragment ions profiling and multiple reaction monitoring mass spectrometry with high resolution assays revealed a significant downregulation of CYP2C27 and CYP2D20 in pparα−/− hamsters. Enzymatic kinetic assays demonstrated reduced activity for several enzymes, including CYP1A2 (involved in the metabolism of acetaminophen), CYP2C family (responsible for 4′-hydroxy diclofenac formation), CYP2D family (involved in dextrorphan production), CYP2E1 (involved in 6-hydroxy chlorzoxazone production), and UGTs (responsible for chenodeoxycholic acid 24-acyl-β-D-glucuronide and mycophenolic acid glucuronide formation). These reductions suggest impaired drug metabolism and an increased risk of drug-drug interactions in conditions of reduced pparα function. In contrast, enzymes such as the CYP2B family, CYP3A family, and UGTs involved in N-Acetyl serotonin β-D-glucuronide formation retained their activity, indicating selective pathway preservation in pparα −/− hamsters. These findings highlight the selective regulatory roles of pparα on certain drug-metabolizing enzymes, providing important insights into metabolic regulation in pparα-deficient states.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117339"},"PeriodicalIF":5.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068999","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":"CAMK2G in subcellular Ca2+ homeostasis: Molecular mechanisms and therapeutic targeting","authors":"Yashi Cao ,&nbsp;Zengyue Pan ,&nbsp;Xiner Shen ,&nbsp;Zhifei Xu ,&nbsp;Xiaochun Yang ,&nbsp;Bo Yang ,&nbsp;Peihua Luo ,&nbsp;Hao Yan ,&nbsp;Qiaojun He","doi":"10.1016/j.bcp.2025.117323","DOIUrl":"10.1016/j.bcp.2025.117323","url":null,"abstract":"<div><div>The Ca²⁺/calmodulin-dependent protein kinase II (CAMK2) family, consisting of subtypes A, B, D, and G, plays a pivotal role in decoding Ca²⁺ signals, an essential process in cellular communication and function. Among these, CAMK2G is notably widespread across various body tissues, with predominant expression in neurons and cardiomyocytes, where it significantly influences Ca²⁺ signal transduction and the cellular response to stress. Ca²⁺ serves as the most plentiful second messenger within the human body, orchestrating critical regulatory roles across numerous physiological and pathological contexts. It is instrumental in managing aspects of the tumor microenvironment, neurodegenerative conditions, cardiovascular diseases, and metabolic disorders. Maintaining Ca²⁺ homeostasis is crucial for the proper functioning of different subcellular organelles, impacting overall cellular health and activity. Here, we describe the central connection between CAMK2G and subcellular Ca²⁺ homeostasis, highlight the molecular functions of CAMK2G therein, and finally detail the cutting-edge therapeutic strategies targeting CAMK2G.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117323"},"PeriodicalIF":5.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069004","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":"Promising clopidogrel analogs may overcome clopidogrel resistance: 2025 update.","authors":"Hong-Guang Xie, Li-Ping Jiang, Ting Tai, Yu-Meng Jia, Jin-Zi Ji, Qiong-Yu Mi","doi":"10.1016/j.bcp.2025.117330","DOIUrl":"10.1016/j.bcp.2025.117330","url":null,"abstract":"<p><p>Clopidogrel is one of the World Health Organization-recommended essential medicines used for antiplatelet therapy. However, its usage is limited by resistance of certain patients to clopidogrel. Herein, we systematically summarized promising novel analogs of clopidogrel and evaluated their preclinical and clinical properties as well as the science behind the study. The primary strategy of their design and synthesis is largely focused on how to enhance their metabolic activation, significantly increasing the systemic exposure of their active thiol metabolites (such as H4). Of these, DT-678 released H4 into the blood following exposure to GSH due to bypassing all cytochrome P450-mediated metabolic activation processes of clopidogrel; evategrel (formerly CG-0255) was converted to H4 by esterase-catalyzed hydrolysis. Vicagrel, acetate of clopidogrel, was completely hydrolyzed to 2-oxo-clopidogrel by intestinal hydrolases, thus bypassing the first-step oxidation of clopidogrel and consequently increasing the formation of H4. The same strategies as those for prasugrel and vicagrel were used to design new compounds, such as tipidogrel, compound 6b, PLD-301, and W-1. In addition, 2-oxo-clopidogrel, an intermediate metabolite shared by clopidogrel, vicagrel, PLD-301, and W-1, was used to determine whether it could exert the same antiplatelet effect as its parent drugs. Moreover, clopidogrel and vicagrel were also deuterated to further increase the formation of H4 in the liver. All these new compounds in the pipeline are promising antiplatelet drugs, and superior to clopidogrel. DT-678 and evategrel are considered the best clopidogrel analogs that may overcome clopidogrel resistance due to their superior efficacy and safety profiles over clopidogrel.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117330"},"PeriodicalIF":5.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069078","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":"piR-hsa-35410 promotes triple-negative breast cancer progression via enhancing PFKL mediated glycolysis","authors":"Xiufen Zhang ,&nbsp;Xue Wang ,&nbsp;Jingjing Lu ,&nbsp;Linzi Zeng ,&nbsp;Bujie Xu ,&nbsp;Chaofu Wang ,&nbsp;Zhenglin Wang ,&nbsp;Ping Zhou","doi":"10.1016/j.bcp.2025.117337","DOIUrl":"10.1016/j.bcp.2025.117337","url":null,"abstract":"<div><div>PIWI-interacting RNAs (piRNAs) have been reported to be closely associated with the development and progression of various cancers. However, the role of piRNAs in triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, remains poorly understood. This study identified piR-hsa-35410 (hereafter piR-35410) with aberrant expression and aimed to further elucidate its biological functions and mechanisms in TNBC. In TNBC, the elevated expression of piR-35410 enhanced clone formation and cell migration capacities, as well as glycolytic activity. Mechanistic investigations revealed that piR-35410 interacted with ATP-dependent 6-phosphofructokinase, Liver Type (PFKL), a crucial rate-limiting enzyme in glycolysis, and primarily bound to its truncated isoform encompassing amino acids 470 to 780. piR-35410 enhanced glycolytic capacity in TNBC by regulating Phosphofructokinase (PFK) enzyme activity without affecting PFKL expression. Moreover, our study found that PFKL was highly expressed in TNBC, further augmenting glycolytic activity and the malignant phenotype. Functional rescue experiments provided evidence that piR-35410 drove TNBC malignant progression by regulating PFKL-glycolysis in vitro and in vivo. In summary, our study revealed that piR-35410 promotes the malignant progression of TNBC by regulating PFKL-mediated glycolysis. These findings provide valuable insights into the role of piR-35410 in TNBC pathogenesis, revealing its potential as a novel therapeutic target.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117337"},"PeriodicalIF":5.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069070","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}