Acta Pharmacologica Sinica最新文献

{"title":"The deubiquitinase YOD1 in renal tubular epithelial cells promotes diabetic kidney disease by stabilizing KEAP1.","authors":"Qing-Qing Zhao, Ying Zhao, Shi-Jie Fan, Yu-Cheng Jiang, Ting-Hong Zheng, Shen-Jie Bao, Di-Yun Xu, Zhao-Zheng Zheng, Yan-Hong Jin, Yi Wang, Shu-Yi Chong, Guang Liang, Hong Zhu","doi":"10.1038/s41401-026-01919-1","DOIUrl":"https://doi.org/10.1038/s41401-026-01919-1","url":null,"abstract":"<p><p>Renal tubular epithelial cell (RTEC) injury is an early event in diabetic kidney disease (DKD) and is a key driver of its development and progression. Deubiquitinating enzymes (DUBs) play crucial roles in the progression of diseases by regulating the stability of substrate proteins. This study aims to elucidate the regulatory role and underlying mechanisms of the deubiquitinating enzyme ovarian tumor domain-containing 2 (YOD1) in RTEC injury and DKD. Through transcriptomics and single-cell mRNA sequencing, we confirmed that YOD1 expression is upregulated in diabetic kidneys and that YOD1 is predominantly localized in RTECs. RTEC-specific Yod1 knockout alleviates renal injury in diabetic mice. RNA-seq analysis revealed a positive correlation between YOD1 and the oxidative stress signaling pathway. Interactome analysis revealed the oxidative stress regulatory protein Kelch-like ECH-associated protein 1 (KEAP1) as a YOD1 substrate. YOD1 deubiquitinates and stabilizes KEAP1, which suppresses NRF2 nuclear translocation under high glucose and palmitic acid (HG/PA) stimulation, thus increasing oxidative stress. Similarly, the ROS scavenger N-acetylcysteine (NAC) can alleviate oxidative stress injury to some extent by reducing ROS levels in RTECs. Finally, we confirmed that the YOD1 pharmacological inhibitor G5 has therapeutic effects on kidney injury in diabetic mice. Our findings demonstrate that the YOD1-KEAP1 axis mediates oxidative stress injury in RTECs and highlight that targeting YOD1 represents a potential treatment approach for DKD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis for small-molecule agonism at GCGR and GIPR via a conserved intracellular allosteric site.","authors":"Qian He, Hong Shan, Wen Hu, H Eric Xu, Li-Hua Zhao","doi":"10.1038/s41401-026-01923-5","DOIUrl":"https://doi.org/10.1038/s41401-026-01923-5","url":null,"abstract":"<p><p>The glucagon receptor (GCGR) and gastric inhibitory polypeptide receptor (GIPR) are class B GPCRs that regulate glucose homeostasis and energy balance, making them key targets for type 2 diabetes and obesity. Achieving preferential G_s signaling at these receptors with small molecules remains an unmet challenge. Here, we report SIM1, developed through optimization of the PCO371 scaffold, which exhibits preferential G_s signaling at GCGR and GIPR with minimal detectable β-arrestin recruitment and substantially improved efficacy at GIPR. Cryo-EM structures of SIM1-GCGR-G_s (2.53 Å) and SIM1-GIPR-G_s (2.74 Å) reveal a shared intracellular allosteric interface at the receptor-G protein coupling region, distinct from extracellular peptide recognition. Structural comparison with GLP1R suggests that intracellular conformational constraints contribute to differential SIM1 responsiveness, which is restored by targeted mutations. Guided by these insights, analogs SIM2 and SIM3 exhibited up to 20-fold enhanced potency while maintaining an apparent preferential G_s signaling profile. These findings reveal a conserved intracellular allosteric activation mechanism across multiple class B GPCRs and identify SIM1 and its analogs as valuable chemical tools for investigating receptor-specific intracellular allosteric regulation and G protein-preferential signaling.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The RNA structural code: orchestrating gene expression and enabling precision therapies.","authors":"Nan-Nan Fang, Qu-Bo Zhu","doi":"10.1038/s41401-026-01925-3","DOIUrl":"https://doi.org/10.1038/s41401-026-01925-3","url":null,"abstract":"<p><p>Following transcription, RNA undergoes hierarchical folding mediated by base pairing and long-range interactions, forming diverse dynamic structures such as local helices, loops, bulges, pseudoknots, G-quadruplexes, riboswitches, and higher-order conformations. These structures function as molecular switches that are recognized by RNA-binding proteins and regulatory factors, thereby precisely controlling the spatiotemporal dynamics of posttranscriptional gene expression. Emerging evidence indicates that aberrant RNA structural dynamics are closely associated with diverse human diseases. RNA-targeted therapeutic strategies, characterized by high specificity, programmability, and broad potential, have emerged as a promising next-generation therapeutic modality beyond conventional small-molecule and antibody-based therapies. Although current RNA-targeted approaches have focused primarily on gene silencing, strategies for enhancing endogenous gene expression are increasingly demonstrating substantial translational potential. In this review, we systematically summarize posttranscriptional gene regulation mechanisms mediated by RNA structural diversity, with a particular emphasis on the roles of RNA structures in alternative splicing, RNA localization and transport, translation, and RNA degradation. We further discuss recent advances, current challenges, and emerging clinical prospects of RNA-targeted therapeutic strategies in human diseases. Overall, this review provides a comprehensive overview of RNA structure‒function relationships and highlights their implications for precision medicine and the development of next-generation RNA-based therapeutics.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic cancer vaccines: development, challenges, and future perspectives.","authors":"Di Di, Luan-Feng Li, Tian-Yang He, Hong-Xia Cui, Yue Nian, Xue Jiao, Cui-Yan Han, Min-Jie Wei","doi":"10.1038/s41401-026-01928-0","DOIUrl":"https://doi.org/10.1038/s41401-026-01928-0","url":null,"abstract":"<p><p>Therapeutic cancer vaccines are designed to induce tumor-specific immunity and durable antitumor surveillance. However, their clinical efficacy remains limited by antigen heterogeneity, defective antigen presentation, immune exhaustion, and immunosuppression within the tumor microenvironment (TME). Advances in sequencing, immunopeptidomics, artificial intelligence (AI)-assisted neoantigen prioritization, nucleic acid engineering, dendritic cell (DC) biology, and combination therapy have shifted the field from empirical antigen exposure toward mechanism-guided vaccine design. This review outlines the historical development of therapeutic cancer vaccines, neoantigen identification strategies, and recent progress in DNA, RNA, peptide, cellular, and viral vaccine platforms. Key mechanisms shaping vaccine response and resistance are also discussed, including pattern-recognition receptor (PRR) signaling, dendritic cell-mediated antigen presentation, T-cell effector and memory differentiation, metabolic adaptation, epitope spreading, and TME remodeling. Future therapeutic cancer vaccines should be developed as integrated immunological systems that coordinate antigen discovery, precise delivery, innate immune calibration, memory maintenance, and local immune suppression reversal to achieve reproducible clinical benefit.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3-Hydroxydehydroleucodin ameliorates neuroinflammation and ischemic brain injury by blocking the TRIM21-PRDX1 interaction.","authors":"Kui Liu, Ling Wang, Zhuo Chen, Yu-Xuan Qiu, Jia-Hong Gao, Ting-Ting Xie, Yue Li, He Huang, Yang Hu, Li-Hong Hu, Tao Pang","doi":"10.1038/s41401-026-01922-6","DOIUrl":"https://doi.org/10.1038/s41401-026-01922-6","url":null,"abstract":"<p><p>Ischemic stroke triggers profound neuroinflammation and autophagic stress, driven predominantly by microglial overactivation. However, effective therapies targeting this pathogenesis remain elusive. Here, we report the use of 3-hydroxydehydroleucodin (3-Hyd), the primary active component from Kudiezi injection used in China for ischemic stroke patients, as a potent neuroprotective agent that markedly reduces the cerebral infarct area and improves neurological deficits in a mouse model of transient middle cerebral artery occlusion (tMCAO). Integrated bulk RNA sequencing and in vitro assays revealed that 3-Hyd significantly suppressed the microglial proinflammatory phenotype and excessive autophagic flux. Mechanistically, through chemical biology approaches, we discovered that 3-Hyd directly binds to the V51 and R128 residues of peroxiredoxin 1 (PRDX1), which physically disrupts the pathological binding of PRDX1 to its E3 ubiquitin ligase TRIM21, thus preventing the polyubiquitination of PRDX1 at the K109 residue and its subsequent proteasome degradation. Consequently, stabilized PRDX1 impedes TRAF6 ubiquitination, effectively blocking the downstream NF-κB signaling cascade. Strikingly, the anti-neuroinflammatory and cerebroprotective effects of 3-Hyd were largely abolished in microglia-specific Prdx1 conditional knockdown (Cx3cr1^Cre/ERT2) mice. Together, our findings elucidate a novel TRIM21-PRDX1-TRAF6 signaling axis that governs microglial homeostasis and highlight the pharmacological stabilization of PRDX1 by 3-Hyd to block the binding of TRIM21 with PRDX1 as a promising therapeutic strategy for ischemic stroke.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis of β-arrestin coupling and transducer selectivity in PAC1R.","authors":"Min Zhang, Xin Li, Qing-Ning Yuan, Wen Hu, H Eric Xu, Li-Hua Zhao","doi":"10.1038/s41401-026-01924-4","DOIUrl":"https://doi.org/10.1038/s41401-026-01924-4","url":null,"abstract":"<p><p>The pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a class B G protein-coupled receptor (GPCR) that engages both G proteins and β-arrestins to mediate diverse signaling responses, yet how PAC1R adopts distinct intracellular conformations to achieve this transducer selectivity remains poorly understood. Here, we report the cryo-electron microscopy structure of PAC1R in complex with β-arrestin 1 (βarr1), revealing a core-engaged conformation. Comparison with the G_s-bound PAC1R structure shows that βarr1 engagement is associated with remodeling of the intracellular transmembrane bundle, including TM5 reorientation and inward movement of TM6, resulting in a receptor core geometry distinct from that of the G protein-bound state. Comparison with the βarr1-bound parathyroid hormone receptor 1 (PTH1R) structure further reveals both conserved and receptor-specific features of βarr1 engagement. Although outward displacement of the TM5 cytoplasmic end is observed in both PAC1R-βarr1 and PTH1R-βarr1 complexes, its specific direction and the resulting TM5-TM6 rearrangements differ between receptors, correlating with distinct βarr1 finger loop orientations within the receptor core. Together, these findings suggest that β-arrestin core engagement by class B GPCRs is accompanied by receptor-specific intracellular remodeling that may contribute to transducer selectivity in PAC1R.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148904893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vasohibin 1 acts as a key regulator of arrhythmogenesis in pressure-overload-induced cardiac hypertrophy.","authors":"Gang Wang, Yu-Juan Song, Wen-Lin Yuan, Mei-Yu Hu, Jia Liu, Yan-Jiao Li, Ji-Dong Chen, Yun-Xiang Sun, Wan-Wen Cheng, Ying Li, Cheng-Lin Zhang, Wen-Juan Liu, Wei-Hua Wu, Hui Tan, Jie Liu","doi":"10.1038/s41401-026-01884-9","DOIUrl":"https://doi.org/10.1038/s41401-026-01884-9","url":null,"abstract":"<p><p>The morphology and dynamics of microtubules (MTs) are controlled by the posttranslational modification of tubulins and are critical for maintaining cardiac electrophysiological homeostasis. Recent studies have revealed that vasohibin (VASH) is a detyrosinating enzyme of tubulin, and the upregulation of VASH1 (the dominant VASH isoform in the heart) induces MT detyrosination and impaired cardiac function. It remains unknown whether VASH1 participates in the pathogenesis of ventricular arrhythmia, a lethal pathological change in cardiac hypertrophy. Here, we demonstrated that significantly increased expression of VASH1 and detyrosinated α-tubulin led to greater susceptibility of the heart to ventricular arrhythmia, as indicated by an increased number of caffeine and isoproterenol-stimulated premature ventricular complexes (PVCs) on electrocardiography in transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice versus Sham mice. Cardiac-specific VASH1 overexpression induced MT detyrosination and polymerization, increasing the number of stimulated PVCs in normal mice. Optical mapping of the hearts demonstrated that VASH1 overexpression slowed electrical conductance. A mechanistic study revealed that VASH1 upregulation increased the Ca²⁺ spark frequency and post-pacing Ca²⁺-release events, disrupted the transverse tubule network, and altered the distribution of connexin-43 at gap junctions. In cultured cardiomyocytes, VASH1 overexpression similarly increased Ca²⁺ spark generation, which was abolished by the coexpression of tubulin tyrosine ligase (TTL) but not by TTL-E331Q, a mutant that lacks TTL catalytic activity but maintains its depolymerization effect. Furthermore, ablation of VASH1 decreased the susceptibility of TAC mice to ventricular arrhythmia by reducing the expression of arrhythmogenic substrates. In this study, we identified VASH1 as a master regulator of arrhythmogenesis in cardiac hypertrophy, reinforcing this protein as a promising therapeutic target for preventing ventricular arrhythmia.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BioPROTACs: a promising approach for targeted protein degradation.","authors":"Yu-Yang Li, Fu-Ru Zhang, Ren-Shuai Zhang, Dong-Ling Shao, Li-Li Yang, Xin-Yu Wang, Xue-Wei Cao, Shu-Ang Sun, Rui-Xin Ge, Song-Bo Xie","doi":"10.1038/s41401-026-01918-2","DOIUrl":"https://doi.org/10.1038/s41401-026-01918-2","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) has emerged as an important therapeutic strategy in recent years. Proteolysis-targeting chimeras (PROTACs) are among the most extensively studied TPD technologies that eliminate target proteins through a \"degradation rather than inhibition\" mechanism. This mechanism offers opportunities to target proteins that are difficult to modulate using conventional small-molecule inhibitors and may also help mitigate drug resistance. However, the development of small-molecule PROTACs remains constrained by challenges associated with druggability, target accessibility, E3 ubiquitin ligase availability, and clinical translation. BioPROTACs have subsequently emerged as an alternative degradation platform in which genetically encoded protein modules replace conventional small-molecule ligands while preserving the underlying degradation mechanism. Their molecular design enables broader target recognition, flexible E3 ligase recruitment, and improved molecular specificity. Their emerging applications span cancer, viral infections, and neurodegenerative diseases. This review summarizes the molecular mechanisms, recent advances, and emerging applications of bioPROTAC technology, evaluates the current technical challenges, discusses potential strategies to address these limitations, and highlights future directions that may facilitate its clinical translation.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYFIP2 deficiency ameliorates renal interstitial fibrosis through attenuating tubular senescence in hypertensive nephropathy.","authors":"Ming-Chen Sun, Fu-Wen Zuo, You-Zhao Wang, Xiu-Li Ren, Hong-Shen Lu, Ming-Bo Zheng, Hao-Ran Zhang, Han-Lin Liu, Cui-Cui Lu, Cheng-Wu Shen, Ji-Chao Wu","doi":"10.1038/s41401-026-01793-x","DOIUrl":"10.1038/s41401-026-01793-x","url":null,"abstract":"<p><p>Tubulointerstitial fibrosis is the central pathological feature of hypertensive nephropathy, with cellular senescence being a key driver. Therefore, identifying therapeutic targets in senescent renal tubular epithelial cells is clinically important. The cytoplasmic FMR1-interacting protein (CYFIP) family, which comprises two evolutionarily conserved members, CYFIP1 and CYFIP2, plays crucial roles in neurological regulation. CYFIP2, a key member, is implicated in cytoskeletal dynamics and apoptosis within the nervous system; however, its renal expression pattern and function remain undefined. This study revealed that CYFIP2 expression was significantly upregulated in the renal cortex, particularly in the proximal tubules, of DOCA/salt-induced hypertensive mice, and was positively correlated with the extent of fibrosis. Consistently, CYFIP2 was highly expressed in the renal tubules of patients with hypertensive nephropathy, where its level inversely correlated with the estimated glomerular filtration rate (eGFR). Tubule-specific deletion of CYFIP2 attenuated hypertension-induced cellular senescence (reduced SA-β-gal, p53/p21, and SASP; increased Klotho) and mitigated renal dysfunction, collagen deposition, and epithelial‒mesenchymal transition (EMT). In vitro, CYFIP2 silencing alleviated TGF-β1-induced senescence and fibrosis in HK-2 cells. Mechanistically, CYFIP2 and p53 formed a positive feedback loop that promoted fibrosis by inhibiting the Hippo pathway and enhancing YAP nuclear translocation. The p53 agonist Nutlin-3a reversed the protective effect of CYFIP2 knockout, while the inhibitor Pifithrin-α mimicked this effect. These findings underscore the pivotal role of the CYFIP2/p53-Hippo/YAP axis in hypertensive renal injury, and identify CYFIP2 as a potential therapeutic target. CYFIP2/p53-Hippo signaling drives tubular senescence and renal fibrosis in hypertensive nephropathy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2554-2568"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP-mediated mechanotransduction promotes hepatocellular carcinoma progression by targeting ATP1A1/CXCL1 axis.","authors":"Meng-Nan Zhang, Xin-Peng Wen, Jing-Yi Liu, Ying Xiong, Makoto Miyagishi, Vivi Kasim, Shou-Rong Wu","doi":"10.1038/s41401-026-01916-4","DOIUrl":"https://doi.org/10.1038/s41401-026-01916-4","url":null,"abstract":"<p><p>Extracellular matrix (ECM) stiffness is a critical biomechanical factor that plays a key role in tumor progression, influencing tumor behavior and driving its malignancy. Transcriptional co-activator yes-associated transcriptional regulator (YAP) is a well-established mechanosensitive regulator; however, the molecular mechanisms by which matrix stiffness-mediated YAP activation promotes tumor progression through transcriptional regulation remain incompletely defined. Here, using cross-omics analysis, in vitro, and in vivo experiments, we identified ATPase Na⁺/K⁺ transporting subunit alpha 1 (ATP1A1) as a novel target of YAP/TEA domain transcription factor 4 (TEAD4) mechano-responsive transcription factor complex, whose increased expression in stiff matrix promotes tumor cell proliferation. Mechanistically, we revealed that stiff matrix promotes YAP/TEAD4 binding to the ATP1A1 promoter, thereby upregulating its expression. Increased ATP1A1 in turn promotes intracellular calcium signaling and activates the nuclear factor-kappa B (NF-κB) pathway, thereby promoting C-X-C motif chemokine ligand 1 (CXCL1) expression and secretion, and subsequently enhances tumorigenic potential. These findings demonstrate that increased matrix stiffness activates YAP/TEAD4-dependent transcriptional program and promotes ATP1A1 expression, thereby converting mechanical cues into chemical signaling output and finally promoting malignant phenotypes in the tumor. Furthermore, these findings suggest that CXCL1 may contribute to stiffness-associated tumor progression and warrant further investigation as a potential therapeutic target.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}