Signal Transduction and Targeted Therapy最新文献

{"title":"The histone deacetylase family in health and disease.","authors":"Ri Wen, Yu-Hang Yang, Tao Zhang, Sen-Yu Zhang, Xin-Ru Yang, Li-Ying Zhang, Peng-Hui Hao, Yue Zheng, Ni Yang, Tie-Ning Zhang","doi":"10.1038/s41392-026-02764-8","DOIUrl":"10.1038/s41392-026-02764-8","url":null,"abstract":"<p><p>Zinc-dependent classical histone deacetylases, including Classes I, II, and IV, are ubiquitously present in mammals and play vital roles in numerous biological processes. To date, eleven histone deacetylase members have been identified, namely, histone deacetylase 1 through histone deacetylase 11. A growing body of evidence underscores the crucial roles of these histone deacetylase members in both physiological and pathological conditions. Notably, these histone deacetylase members are involved in various cellular processes, including inflammation, metabolism, apoptosis, and oxidative stress. Consequently, histone deacetylases have emerged as promising therapeutic targets for a range of pathological conditions, including tumors, cardiovascular diseases, and neurological disorders. Moreover, the development of histone deacetylase modulators, which can regulate their activity, has shown significant therapeutic potential across various conditions. Several histone deacetylase inhibitors have been approved by the U.S. Food and Drug Administration for the treatment of multiple tumors and Duchenne muscular dystrophy, while many others are being developed for oncology and other therapeutic applications. In this review, we introduce the research history and structural characteristics of histone deacetylases. We then summarize the molecular mechanisms and biological functions of the eleven histone deacetylase family members. Moreover, we elucidate the critical regulatory roles of histone deacetylases in various human diseases. Furthermore, we provide an overview of histone deacetylase modulators, their current clinical applications, and potential benefits, offering insight into the regulation of histone deacetylases for the treatment of related diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971131","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":"Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK.","authors":"Yang Yang, Hui Chen, Shensi Xiang, Yujia Wei, Limin Zhang, Aihua Sun, Xiao E, Fan Wu, Ning Luo, Fei Liang, Xiaojie Wu, Chenyu Wang, Zhuo Chen, Qizheng Zhang, Xinrui Chen, Qinlu Wu, Zixuan Han, Changyan Li, Ronghua Yin, Guangming Ren, Jingjing Li, Ke Zhao, Huiying Gao, Ruijia Wang, Miao Yu, Xiaoming Yang","doi":"10.1038/s41392-026-02773-7","DOIUrl":"10.1038/s41392-026-02773-7","url":null,"abstract":"<p><p>Liver aging significantly impairs hepatic function and regenerative capacity, increasing the risk of morbidity and mortality from chronic liver diseases. Identifying molecular regulators of these processes may reveal promising therapeutic targets. Although Hepassocin (HPS), a hepatokine with known hepatoprotective functions, has minimal effects on liver homeostasis in adult mice, its role in long-term liver maintenance remains unclear. In this study, we observed a decrease in circulating and intrahepatic HPS levels in both aged mice and elderly humans. Moreover, the upregulation of HPS following two-thirds partial hepatectomy (PHx) was significantly blunted in 12-month-old (aged) mice. Aged HPS-knockout (KO) mice exhibited variable hepatic steatosis, exacerbated cellular senescence, and impaired autophagy. Liver regeneration after PHx was severely compromised in aged HPS-KO mice, as indicated by increased mortality, reduced hepatocyte proliferation, delayed liver mass recovery, and worsened autophagy disruption. Mechanistically, HPS directly activated 5'-AMP-activated protein kinase catalytic subunit alpha-1 (AMPK) in hepatocytes via the Annexin A2 (ANXA2)-extracellular signal-regulated kinase 2-90 kDa ribosomal protein S6 kinase 1-liver kinase B1 (ANXA2-ERK-p90RSK-LKB1) signaling cascade. Compared with their wild-type littermates, aged HPS-KO mice presented reduced LKB1 and AMPK activation and elevated mechanistic target of rapamycin kinase (mTOR) activity in both quiescent and regenerating livers. Treatment with the AMPK agonist AICAR ameliorated the liver aging phenotype and restored liver regenerative capacity in aged HPS-KO mice. Importantly, the administration of exogenous HPS enhanced regenerative outcomes in aged wild-type mice. These results establish HPS as a novel protective factor against liver senescence through AMPK-dependent mechanisms. Therapeutic strategies aimed at enhancing HPS signaling may offer a viable approach to counteract age-related liver dysfunction and regeneration failure.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971141","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":"Interleukin-1 receptor-associated kinase 1 controls chemoresistance and immuno-killing in non-small cell lung cancer.","authors":"Sabrina Digiovanni, Claudia Giannotta, Luca Alessandri, Simona Fontana, Angelo Meoli, Paolo Bironzo, Alessandra Merlini, Gabriella Doronzo, Parab Sushant, Elisa Balmas, Muhlis Akman, Joanna Kopecka, Maddalena Arigoni, Francesca Napoli, Julia Wens, Samuele Tarallo, Alessandro Bertero, Stefano Guglielmo, Barbara Rolando, Davide Palma, Luisella Righi, Massimo Massaia, Raffaele Calogero, Federico Bussolino, Silvia Novello, Giorgio Vittorio Scagliotti, Iris Chiara Salaroglio, Chiara Riganti","doi":"10.1038/s41392-026-02848-5","DOIUrl":"10.1038/s41392-026-02848-5","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) shows partial chemoimmunoresistance, driven by the upregulation of the drug efflux transporters ABCB1 and ABCC1 and the downregulation of the immunosensitizer protein ABCA1. To elucidate the molecular mechanisms underlying this chemoimmunoresistant phenotype, by performing a CRISPR-KO kinome screening, we identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a key determinant of chemoimmunosensitive and chemoimmunoresistant phenotypes, defined as ABCB1/ABCC1^lowABCA1^high and ABCB1/ABCC1^highABCA1^low, respectively. IRAK1 expression was significantly associated with poor prognosis in the TCGA-LUAD cohort and in early-stage NSCLC patients. The IRAK1/ABCB1/ABCC1^highABCA1^low signature was predictive of poor response to chemotherapy and immunotherapy in advanced-stage patients. Mechanistically, IRAK1 silencing resensitized NSCLC cells to cisplatin by decreasing IL-1R/NFκB and IL-1R/AP-1 signaling, which in turn downregulated the drug efflux transporters ABCB1 and ABCC1. Concurrently, IRAK1 silencing activated the LXRα/ABCA1 axis, which enhanced Vγ9Vδ2 Tcell-mediated cytotoxicity and facilitated the recruitment of memory and effector CD4⁺ and CD8⁺ T cells in both ex vivo autologous cocultures and immunoxenografts, increasing the immuno-killing ability of tumor cells. Newly developed synthetic inhibitors of IRAK1 efficiently promoted chemo- and immunosensitization in immunoxenografts, resulting in good pharmacokinetic and safety profiles. These findings identify IRAK1 as a novel, druggable target that controls both chemoresistance and immune evasion in NSCLC. We suggest the pharmacological inhibition of IRAK1 as a future promising strategy to overcome resistance to chemotherapy and improve patient outcomes.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971119","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":"IFNAR1-dependent metabolic circuit drives pathogenic neutrophil activation in chronic mucosal inflammation.","authors":"Cecilia Pessoa Rodrigues, Raquel R Calçada, Mafalda Arnaud, Lukas Kaltenbach, Mika Manser, Anja Scheidegger, Leon Sidney Strauss, Alina Gavrilov, Sharang Kulkarni, Ece Yildiz, Daniela Liberati, Mairene Coto-Llerena, Tamara Hoening, Markus Martin Kramberg, Julian Behr, Anna Mechling, Marvin Hering, Kara G Lassen, Oliver Soehnlein, Emma Doran, Daniel Regan-Komito","doi":"10.1038/s41392-026-02963-3","DOIUrl":"10.1038/s41392-026-02963-3","url":null,"abstract":"<p><p>Neutrophils are double-edged effectors of the innate immune system: while essential for host defense, they can drive significant tissue damage in the context of chronic inflammatory diseases. Identifying strategies to selectively dampen their pathogenic functions without compromising antimicrobial immunity remains a major clinical challenge. Here, we define a conserved IFNAR1-driven circuit mediated by iron homeostasis that sustains neutrophil pathogenicity across distinct mucosal tissues. Using single-cell transcriptomics and a CRISPR-based functional screen, we identified the mitochondrial iron transporter Mitoferrin-1 (SLC25A37) as a key regulator of neutrophil inflammatory programming. Mechanistically, our data indicate that Mitoferrin-1 mediates a feedforward loop in which NET-derived histones activate toll-like receptor 9 (TLR9), which in turn sustains IFN-α/IFNAR1 signaling, rewires mitochondrial metabolism, and ultimately drives tissue damage through markedly increased of NETosis, reactive oxygen species production, and degranulation. Notably, this IFNAR1-driven inflammatory circuit operates entirely independently of antimicrobial function, as pharmacological IFNAR1 blockade fully preserves phagocytic activity against bacterial pathogens in vivo. Targeting this pathway selectively attenuates neutrophil-driven inflammation in both murine models of colitis and acute lung injury, as well as in primary human intestinal organoid systems. Together, these findings identify a targetable metabolic node for selectively disarming pathogenic neutrophil responses in the setting of chronic inflammatory disease.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963693","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":"Ferroptosis blockade: beyond preservation to active graft therapy.","authors":"Chen Xing, Gabriel C Oniscu, Volker M Lauschke","doi":"10.1038/s41392-026-02996-8","DOIUrl":"10.1038/s41392-026-02996-8","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963700","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":"Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes","authors":"Jakob Höppner,Harald Jüppner,Monica Reyes,Prem Swaroop Yadav,Dian Wang,Thomas Dean,Patrick Hanna,Roberto Civitelli,Asuka Inoue,Ernestina Schipani,Ignacio Portales-Castillo,Thomas J. Gardella","doi":"10.1038/s41392-026-02795-1","DOIUrl":"https://doi.org/10.1038/s41392-026-02795-1","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"377 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923067","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":"Malic enzyme 1 senses L-lactate to determine tumor heterogeneity","authors":"Si-Yi Cao,Kewen Hu,Shijing Huang,Xiao-Lin Guan,Jian Wang,Yuan Shen,Hui Ming,Aihong Gu,Chao Wang,Xiao Shen,Qing Wu,Zhengjun Chen,Miao Yin,Wenyu Wen,Qun-Ying Lei","doi":"10.1038/s41392-026-02839-6","DOIUrl":"https://doi.org/10.1038/s41392-026-02839-6","url":null,"abstract":"Abstract L-lactate is generally elevated in tumors and acts as a signaling molecule that promotes tumor progression. Here, we reveal that malic enzyme 1 (ME1) functions as a previously unrecognized sensor of L-lactate through direct binding at arginine 155 (R155), thereby potentiating malignancy. Mechanistically, L-lactate binding promotes the nuclear translocation of ME1, a process involving reduced acetylation at lysine 362 (K362) and facilitated by nuclear import of karyopherin-α 4 (KPNA4). Nuclear accumulation of ME1 enhances metastatic potential, which is correlated with increased interaction with hepatoma-derived growth factor (HDGF) and acquisition of an epithelial‒mesenchymal transition (EMT)-related phenotype. Under nutrient-deficient conditions, L-lactate promotes the assembly of a ME1-lactate dehydrogenase B (LDHB) complex, which enhances oxidative phosphorylation (OXPHOS) and increases ATP production, suggesting a metabolic adaptive mechanism that supports tumor cell survival. Notably, the ME1 R155A mutation, which disrupts L-lactate binding, abolishes the protumorigenic effect of the L-lactate-ME1 axis on tumor progression in vivo. In conclusion, our findings identify ME1 as a direct sensor of L-lactate and support a model in which lactate-mediated signaling and metabolic adaptation converge on ME1 to regulate tumor cell plasticity in a context-dependent manner under heterogeneous metabolic conditions. These insights advance our understanding of the spatiotemporal control of metabolic adaptation in cancer and reveal a potential therapeutic target.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"467 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923069","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":"Insulin-like growth factor receptor signaling in physiology and disease","authors":"Muhammad Dilawar,Anoosha Malik,Junguang Liao,Panpan Shen,Ziyi Huang,Pengxiang Zhang,Jiaqi Wang,Nenghua Zhang,Muhammad Farrukh Nisar,Guiqian Chen","doi":"10.1038/s41392-026-02843-w","DOIUrl":"https://doi.org/10.1038/s41392-026-02843-w","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"267 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923068","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":"A randomized, double-blind, active-controlled phase 3 multicenter trial of rHSA for cirrhotic ascites.","authors":"Jidong Jia, Yajun An, Xiaojuan Ou, Weijia Duan, Yongzhong Li, Yong Deng, Jun Xie, Qinghai Wang, Xing Li, Zhongwei Pan, Yawen Luo, Lijia Wang, Xuanfang Zhong, Dajun Wu, Zhongji Meng, Zhirong Liu, Zonghua Chen, Liang Hong, Yali Zong, Yingmei Tang, Lihua Zhong, Cheng Wo, Bin Xu, Baolian Shu, Fei Shi, Guangming Li, Guangming Xiao, Fengqian Song, Guoqiang Zhang, Haiyan Chen, Aijun Liao, Hongjian Wei, Junyi Li, Xuan An, Fangfang Li, Chenwei Pan, Jie Pan, Zhanzhou Lin, Wei Hou, Hong Li, Jianyong Chen, Xiaoping Wu, Shuilin Sun, Yueming Shen, Xiaoqu Zhu, Bin Chen, Yuehong Zeng, Xingguo Xiao, Jiawei Geng, Heng Zhang, Caiyan Zhao, Lu Chen, Qinfang Wu, Yang Li, Xiongxiang Liu, Xueqiang Jiang, Hui Tian, Zhongkuo Li, Ming Zhao, Huai Li, Xiaobo Xiong, Rui Yao, Li Shao, Fengzhu Liu, Lirong Fu, Youwei Liao, Tao Guan, Xinhua Luo, Wenfang Yuan, Hongbo Ji, Xiaolin Zhou, Yongzhang Luo","doi":"10.1038/s41392-026-02951-7","DOIUrl":"10.1038/s41392-026-02951-7","url":null,"abstract":"<p><p>In this multicenter, randomized, double-blind, active-controlled phase 3 trial (NCT06553456), we assessed the equivalence of recombinant human serum albumin (rHSA) expressed in Pichia pastoris to plasma-derived human serum albumin (pHSA) for elevating serum albumin (ALB) levels and non-inferiority regarding ascites improvement in patients with cirrhotic ascites. Using a rigorous dual-endpoint design, the primary endpoint was the change from baseline in serum ALB immediately after the final intravenous infusion. The key secondary endpoint was the ascites improvement rate after the final administration. Ultimately, 364 out of 390 patients completed the study. Statistical equivalence was established for the primary endpoint, with least-squares mean ALB changes of 11.16 ± 0.364 g/L (rHSA) and 10.95 ± 0.395 g/L (pHSA) (LSM difference: 0.21 g/L [95% CI: -0.75, 1.16]). For the secondary endpoint, ascites improvement was non-inferior, demonstrating a 58.0% response rate for rHSA versus 48.7% for pHSA (difference: 9.4% [95% CI: -0.56%, 19.10%]). Both endpoints of the trial were successfully achieved. The overall incidence of adverse events was similar in the two groups; crucially, no anti-drug antibodies were detected in the rHSA group. Exploratory analysis revealed that rHSA significantly reduced glycated ALB (-12.24%), whereas pHSA increased it ( + 12.52%) (P < 0.001). Corroborated by LC‒MS characterization, silver-staining purity assessment, and four biochemical quality attributes (free thiol, Hcy, AGEs, and carbonyl levels), this divergence highlights the preserved molecular integrity of rHSA. This trial demonstrated that in patients with cirrhotic ascites, rHSA was statistically equivalent to pHSA in elevating serum ALB and non-inferior in ascites improvement, with a favorable safety profile.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13588796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002447","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":"Alveolar epithelial depletion of βPAK-interacting exchange factor drives spontaneous pulmonary fibrosis by impairing stemness.","authors":"Han-Byeol Kim, Woogil Song, Sun-Ok Kim, Jin-Hee Park, Junyeol Han, Ok-Jun Lee, Nak-Kyun Soung, Bumhee Yang, Jinwook Choi, Martin Alexander Schwartz, Jeong Seok Lee, Eun-Young Shin, Eung-Gook Kim","doi":"10.1038/s41392-026-02849-4","DOIUrl":"10.1038/s41392-026-02849-4","url":null,"abstract":"<p><p>Aberrant repair/regeneration of alveolar epithelial stem cells is a key driver of pulmonary fibrosis (PF). While βPAK-interacting exchange factor (βPIX) is connected to stem cell signaling, its role in pulmonary fibrosis (PF) remains unknown. Here, we generated conditional βPIX knockout mice to investigate its contribution to PF pathogenesis. Selectively depleting βPIX in alveolar type 2 (AT2) cells led to progressive PF in mice, recapitulating the key features observed in human idiopathic pulmonary fibrosis (IPF), where AT2 cells exhibit significantly reduced βPIX levels. Single-nucleus RNA sequencing of the lungs of βPIX-deficient mice revealed the emergence of progenitor cells in a transitional stem cell state with senescent attributes, along with active, collagen-producing myofibroblasts. Mechanistically, the loss of βPIX impaired AT2 cell stemness by downregulating Wnt/β-catenin signaling. AT2 cells from IPF patients also presented reduced levels of β-catenin and Axin2, confirming the downregulation of Wnt/β-catenin signaling. Treatment with a glycogen synthase kinase-3β inhibitor reactivated Wnt/β-catenin signaling and attenuated fibrosis in βPIX-deficient mice. Our results establish a direct causal link between βPIX deficiency and PF, highlighting βPIX and its downstream pathway as promising therapeutic targets for this devastating disease.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920996","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}