Signal Transduction and Targeted Therapy最新文献

{"title":"Endothelial exosomes remodel chromatin accessibility and superenhancer in cancer cells to promote liver metastatic colonization","authors":"Bei Jin, Shenglan Liu, Hongke Huang, Luo Yang, Dong Wei, Wei Dai, Jingfeng Zhou, Yun Wang, Ping Zhang, Qianyun Ye, Jingxuan Pan","doi":"10.1038/s41392-026-02876-1","DOIUrl":"https://doi.org/10.1038/s41392-026-02876-1","url":null,"abstract":"Liver-organotropic metastasis occurs in cancers such as uveal melanoma (UM) and pancreatic ductal adenocarcinoma (PDAC) and is a leading cause of mortality at the terminal stage. Colonization is a rate-limiting and converging step in the metastatic cascade. The drivers underlying liver colonization have largely remained elusive. In this report, we hypothesized that pioneer transcription factors (TFs) increase chromatin accessibility and superenhancer (SE) remodeling, which subsequently promote colonization-associated cellular features [e.g., proliferation, survival, cancer stem cells (CSCs), motility] by driving the transcription of the respective SE-associated genes. We tested this hypothesis and discovered that the pioneer TF KLF4 promoted chromatin accessibility and SE remodeling by ATAC-seq and ChIP-seq. Chromatin accessibility and SE remodeling significantly increased the transcription of the SE-associated genes MCL1 and RASGRP3, which consequently promoted proliferation, motility, and metastasis. Furthermore, the upregulation of KLF4 expression in UM cells was promoted by RN7SL2-containing exosomes from surrounding endothelial cells. Analysis of clinical datasets revealed that the overexpression of RIG-I, STAT1, KLF4, and RASGRP3 was individually correlated with shorter metastasis-free survival or overall survival in patients with UM and PDAC. In conclusion, the identification of the exoRN7SL2-STAT1-KLF4-SEs-RASGRP3 signaling axis may help elucidate metastatic colonization through interactions between tumor cells and the endothelial niche and may yield novel and viable therapeutic targets.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"482 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218148","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":"Next-generation natural killer cell therapy: bench to bedside and beyond.","authors":"Aiqi Zhao, Jing Xu, Wenhai Deng, Minghuan Zhang, Yanping Shao, Yu Liu, Aibin Liang, Xiaobing Wang, Ting Niu, Wenbin Qian","doi":"10.1038/s41392-026-02911-1","DOIUrl":"10.1038/s41392-026-02911-1","url":null,"abstract":"<p><p>Natural killer (NK) cells have emerged as central players in cancer immunotherapy, progressing from basic discovery to clinically validated platforms over five decades. This review synthesizes the evolving understanding of NK cell biology, including subset heterogeneity, epigenetic regulation, and metabolic control, and, as innovative focal points, intratumoral NK heterogeneity, epigenetic modulation, and intracellular immune checkpoints, forming the foundation for rational therapeutic engineering. We examine the clinical trajectory from unmodified adoptive transfer to cytokine-induced memory-like NK cells and, most transformatively, to chimeric antigen receptor (CAR)-NK cells. Landmark trials have established the remarkable efficacy and superior safety of CAR-NK cells in B-cell malignancies, with recent studies extending these benefits to autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis, demonstrating durable immune reset with a favorable safety profile. Despite these advances, solid tumors remain formidable challenges, hindered by antigen heterogeneity, physical barriers, and a metabolically hostile microenvironment. We therefore analyze next-generation engineering strategies that move beyond single modifications toward systems-level reprogramming, encompassing intrinsic enhancements (cytokine signaling, metabolic fitness, checkpoint disruption), extrinsic tumor microenvironment remodeling, and advanced delivery platforms. We further synthesize the practical dimensions of clinical translation by systematically examining key optimization parameters that will guide the path toward precision NK cell therapy. These include rational dosing and scheduling regimens, strategies to reduce lymphodepletion intensity, context-dependent persistence requirements across different disease indications and the emerging biomarker landscape.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196862","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":"Epigenetic regulation of humoral immunity: molecular mechanisms, diseases and therapeutic targets.","authors":"Shaocun Zhang, Yu Wang, Xin Min, Yuzhang Wu, Wanli Liu","doi":"10.1038/s41392-026-02955-3","DOIUrl":"10.1038/s41392-026-02955-3","url":null,"abstract":"<p><p>Humoral immunity, a fundamental branch of adaptive immunity, relies on B lymphocytes and the antibodies they produce to eliminate extracellular pathogens and neutralize toxins. The development, activation, and differentiation of B cells are tightly regulated by epigenetic mechanisms-including DNA methylation, histone modifications, chromatin dynamics, RNA modifications, and noncoding RNAs-that modulate gene expression without altering the DNA sequence, orchestrating key events such as V(D)J recombination, class switch recombination, somatic hypermutation, germinal center reactions, and the generation of memory B cells and plasma cells. In this review, we summarize how these five categories of epigenetic regulators-together with their respective writers, erasers, readers, and effectors-including DNMT3A/3B and TET enzymes, histone-modifying enzymes, SWI/SNF and INO80 remodeling complexes, N6-methyladenosine and 5-methylcytosine machineries, and microRNAs and long noncoding RNAs-collectively govern B-cell fate decisions, from early lineage commitment in the bone marrow, through germinal center dynamics, to terminal differentiation into plasma cells or memory B cells. We further examine how aberrant epigenetic programs in B cells contribute to pathogenesis across four major disease categories: B-cell malignancies, metabolic and cardiovascular diseases, autoimmune disorders, and infectious diseases. We also discuss sex-biased epigenetic mechanisms, particularly escape from X-chromosome inactivation, that may underlie the female predominance of autoimmune diseases. Finally, we discuss the therapeutic implications of targeting epigenetic regulators and assess the potential of epigenetic signatures as biomarkers.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184302","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":"Rescuing anxiety by targeting the neuronal-astrocytic iron signaling axis in male mice.","authors":"Zhuo Wang, Sifan Yang, Shuangyi Tan, Tianrong Huang, Qiong Yang, Juan Fu, Zhen Liu, Baisheng Li, Zuqiang Wu, Junxia Min, Fudi Wang","doi":"10.1038/s41392-026-02921-z","DOIUrl":"10.1038/s41392-026-02921-z","url":null,"abstract":"<p><p>Anxiety disorders affect more than one-quarter of the global population, but current first-line therapies suffer from slow onset and limited efficacy, highlighting the urgent need for novel pathogenic targets. Psychological stress disrupts iron homeostasis in the brain and alters neural circuit excitability; however, the mechanism underlying these two processes remains elusive. Here, we identify a cell type-specific iron signaling pathway between neurons and astrocytes that mediates stress-induced anxiety by regulating synaptic iron transport in the ventral hippocampal-medial prefrontal cortex circuit. In a chronic restraint stress model in male mice, stress induces activity-dependent HMGB1 expression and release from medial prefrontal cortex pyramidal neurons, which bind to astrocytic TLR4 to stimulate local hepcidin secretion. Hepcidin degrades ferroportin at ventral hippocampal-medial prefrontal cortex axonal terminals in a retrograde manner, blocking presynaptic iron efflux. The resultant iron accumulation in ventral hippocampal-medial prefrontal cortex projection neurons increases their intrinsic excitability via a ferroplasticity mechanism and anxiety-like behaviors. Notably, intranasal administration of HMGB1/TLR4 antagonists efficiently restored synaptic iron flux and alleviated anxiety in both stress-induced and innate high-anxiety models. Collectively, our findings define a retrograde ferrosynaptic neuroglial coupling mechanism through which stress induces anxiety independently of classical synaptic transmission. This work establishes the HMGB1-TLR4-hepcidin-FPN axis as a druggable therapeutic target and provides a conceptual framework for understanding how iron metabolism operates as a transcellular social coordination system in emotional regulation.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184331","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":"Rhein-induced free fatty acid generation cooperates with silver ions for biofilm-infected diabetic wound healing.","authors":"Ting Du, Mingrui Cui, Jie Shan, Shan Wang, Shi Chen, Fuchen Song, Qi Li, Liangrong Zhang, Yuemei Zheng, Peiyao Wang, Yanjuan Duan, Jianyong Zhu, Yi Wang, Hanzhi Lu, Xin Liu, Yanbin Zhang, Lei Zhang, Guang Yang, Fulun Li","doi":"10.1038/s41392-026-02869-0","DOIUrl":"10.1038/s41392-026-02869-0","url":null,"abstract":"<p><p>Diabetic foot infection (DFI) significantly increases the risks of hospitalization and amputation, with biofilm infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Escherichia coli (CREC) being key drivers of treatment failure. Here, we analyzed MRSA/CREC biofilm-infected ulcer tissues from patients using proteomics and metabolomics. Compared with nonhealing tissues, healed tissues exhibit activation of low-density lipoprotein receptor (LDLR)-mediated low-density lipoprotein cholesterol (LDL-C) endocytosis and increased free fatty acid production; thus, we hypothesize a potential countermeasure against biofilms. However, the oxidative instability of free fatty acids limits their therapeutic use. Building on our findings demonstrating the potent anti-MRSA/CREC activity of rhein and its synergy with Ag⁺, we developed an injectable hydrogel for sustained codelivery of both agents. This formulation outperforms Ag⁺ monotherapy, accelerating wound closure in biofilm-infected diabetic wounds. Mechanistically, rhein binds to LDLR, upregulates its expression, and enhances the LDL-C endocytosis pathway in vascular endothelial cells to generate more free fatty acids. Among these, eicosapentaenoic acid (EPA) is identified as the most critical free fatty acid that promotes healing, as it inhibits biofilm formation and synergizes with Ag⁺ to exert antibacterial and pro-healing effects. In summary, this study identifies endogenous host lipid metabolites as \"metabolic antibiotics\" and establishes a synergistic therapeutic strategy that concurrently suppresses biofilm formation, inhibits planktonic bacteria, alleviates inflammation, and promotes tissue repair in drug-resistant biofilm-infected diabetic wounds.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184404","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":"Targeting an IL-17/IL-36 pathogenic hub in hidradenitis suppurativa with a bispecific antibody.","authors":"Yonghu Sun, Zihao Mi, Yueqian Yu, Zhenzhen Wang, Lele Sun, Jianke Li, Baoqi Yang, Xiuhuan Wang, Yilei Wu, Kexin Liu, Xiaochen Ren, Jing Liu, Hong Luan, Guowei Zhao, Jian Shi, Chi Ma, Yongxia Liu, Minkuo Zhang, Mingkai Zhang, Peng Song, Peng Qu, Jianfeng Wang, Na Wang, Wenwen Sai, Yue Xin, Qingqing Guo, Weizhi Wu, Na Wang, Hongqing Tian, Xuehui Li, Guoyuan Peng, Xuan Guo, Guangliang Zhang, Xiuqiang Ma, Benke Li, Xiaoxiao Yan, Jianwen Wang, Jiabao You, Gongqi Yu, Chuan Wang, Xiaopei Cui, Yifan Zhan, Xiangyang Zhu, Hong Liu, Furen Zhang","doi":"10.1038/s41392-026-02886-z","DOIUrl":"10.1038/s41392-026-02886-z","url":null,"abstract":"<p><p>Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder with a high unmet need, particularly for treatment-resistant tunnels. Integrated multiomics analysis revealed that HS tunnels are spatially organized, self-amplifying inflammatory circuits driven by synergistic IL-17/IL-36γ activation of a unique keratinocyte subset, which activates neutrophils and inflammatory fibroblasts. This mechanistic insight coupled with spatial coenrichment of IL-17A and IL-36R provided the rationale for HB0043, a bispecific antibody that leverages IL-36R binding to locally dual-block both cytokines. HB0043 outperformed IL-17A/IL-17F bispecific and parental antibodies in vitro. In a proof-of-concept trial (NCT06895499) involving severe, tunnel-dominant Hurley Stage III HS patients, HB0043 induced promising clinical responses. At week 16, patients demonstrated an 82.13% mean percentage reduction from baseline in total abscess and inflammatory nodule count (AN), while 100% and 80% achieved HiSCR50 and HiSCR75, respectively, alongside ultrasound-confirmed tunnel regression and no major short-term safety signals. Longitudinal plasma proteomics showed suppressed inflammation and restored metabolic homeostasis. By tracking these dynamic systemic alterations alongside local structural changes, our multiomics approach bridges the gap between focal tissue lesions and global systemic disease activity. These findings establish dual blockade of IL-17A and IL-36R as a potential therapeutic strategy, offering a targeted strategy for recalcitrant disease that effectively improves the anatomical therapeutic barriers of advanced hidradenitis suppurativa, thereby demonstrating that cross-pathway bispecific antibodies can dismantle complex inflammatory circuits to achieve structural tissue healing where traditional monotherapies consistently fail.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184415","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":"Camrelizumab plus chemotherapy as induction therapy followed by concurrent chemoradiotherapy and camrelizumab consolidation in limited-stage small cell lung cancer: a randomized phase II trial.","authors":"Di Liu, Letong Yang, Min Hu, He Du, Yun Chen, Yaoyao Zhu, Jingjing Kang, Xiaoshuai Yuan, Shuangyan Yang, Qinghua Xu, Shengxiang Ren, Jian Ni, Caicun Zhou, Yaping Xu","doi":"10.1038/s41392-026-02984-y","DOIUrl":"10.1038/s41392-026-02984-y","url":null,"abstract":"<p><p>Definitive chemoradiotherapy followed by immunotherapy consolidation is the current standard of care for limited-stage small cell lung cancer (LS-SCLC). We conducted a randomized phase II trial (ChiCTR2000032275) to evaluate a camrelizumab-based induction-consolidation strategy in previously untreated patients with LS-SCLC. Patients were randomly assigned (1:1) to receive induction camrelizumab plus etoposide-platinum followed by concurrent chemoradiotherapy (CRT) and camrelizumab consolidation (camrelizumab group), or induction chemotherapy followed by concurrent CRT alone (cCRT group). The primary endpoint was the 1‑year progression‑free survival (PFS) rate. Secondary endpoints included objective response rate (ORR), PFS, overall survival (OS), and safety. Between November 2020 and April 2024, 41 patients were enrolled. At a median follow‑up of 32.1 months (interquartile range [IQR]: 26.4-38.7), ORR was 100% in the camrelizumab group and 83.3% in the cCRT group. The 1‑year PFS rates were 65.5% with camrelizumab versus 47.4% with cCRT (P = 0.029). Median PFS was 24.0 months versus 11.8 months, and median OS was not reached versus 23.9 months (P = 0.042). Exploratory biomarker analyses indicated that patients with lower baseline systemic inflammatory indices, including neutrophil-to-lymphocyte ratio <2.8 and platelet-to-lymphocyte ratio <207.0, and those with a decline in lactate dehydrogenase at week 12 after CRT, derived greater benefit from camrelizumab. The OS benefit was also more evident in patients with Ki-67 ≤80%. Toxicities in the camrelizumab group were manageable, with a low incidence of severe immune-related adverse events (4.8%), and radiation pneumonitis rates were comparable between groups. Taken together, induction camrelizumab combined with chemotherapy, followed by CRT and camrelizumab consolidation, significantly improved survival outcomes in LS-SCLC, with a manageable safety profile, warranting further validation for this aggressive malignancy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184306","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":"Acne: epidemiology, risk factors, pathogenesis, management and cutting-edge research.","authors":"Ya Li, Guolin Li, Lian Wang, Dan Du, Jiaqi Li, Deyu Song, Tong Li, Ping Feng, Xian Jiang, Jiong Li","doi":"10.1038/s41392-026-02964-2","DOIUrl":"10.1038/s41392-026-02964-2","url":null,"abstract":"<p><p>Acne vulgaris is a widespread chronic inflammatory skin condition particularly affecting the pilosebaceous unit, with its pathogenesis intricately linked to excessive sebum production, abnormal follicular keratinization, overcolonization by Cutibacterium acnes (C. acnes), and dysregulated host immune responses. Beyond its dermatological manifestations, the disorder is frequently associated with psychological comorbidities such as anxiety and depression, significantly impacting patients' quality of life. A genetic predisposition is evident, with associated polymorphisms involving pathways related to sebaceous gland activity, inflammatory regulation, and hormonal metabolism. Interactions among immune cells, including macrophages and dendritic cells, along with underlying molecular mechanisms, further contribute to its pathogenesis. Conventional acne treatments face challenges such as increasing antibiotic resistance and limited patient adherence. As a result, clinical research and practice are increasingly focusing on targeted, mechanism-based precision strategies. Recent advances in targeted biologics and vaccines directed against C. acnes have demonstrated promise in clinical studies, offering new avenues for acne management. This review provides a systematic overview of the epidemiology, risk factors, diagnostic classifications, and comorbidities associated with acne, with a particular focus on contemporary insights into its immunopathogenesis and molecular mechanisms. Additionally, it synthesizes current treatment modalities and explores emerging directions, such as acne vaccines and biologics, to serve as a reference for further mechanistic investigation and therapeutic advancement.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171687","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":"Pulmonary nodules: classification, biomarkers, signaling pathways, diseases, early diagnosis and management.","authors":"Zhuomiao Ye, Lijun Li, Minghui Zhang, Wei Su, Xin Li, Shoaib Anwaar, Mingyu Xiang, Yulong Yin, Mei Liu, Mingzhu Yin","doi":"10.1038/s41392-026-03103-7","DOIUrl":"10.1038/s41392-026-03103-7","url":null,"abstract":"<p><p>Pulmonary nodules are increasingly detected by thoracic imaging and low-dose computed tomography-based lung cancer screening, but most are benign, transient, or indolent. Clinically, the key task is to distinguish nodules that require timely cancer-directed evaluation from those that can be safely observed. This review summarizes the classification, disease spectrum, risk assessment, early diagnosis, biomarkers, signaling mechanisms, translational models, and management of pulmonary nodules. We first distinguish imaging phenotypes and disease entities, then differentiate the individual-level models used to select candidates for lung cancer screening from the nodule-level models and structured reporting systems used after nodule detection. Low-dose computed tomography remains the foundation of screening and surveillance approaches, whereas magnetic resonance imaging (MRI), positron emission tomography combined with computed tomography, contrast-enhanced computed tomography, nonsurgical biopsy, surgical diagnosis, and local therapies play more selective roles depending on the probability of malignancy and patient fitness. Noninvasive biomarkers, including circulating cellular, nucleic acid, methylation, protein, autoantibody, extracellular vesicle, and metabolic analytes, are most likely to serve as adjuncts to imaging and clinical risk assessment rather than as stand-alone diagnostic tests. Artificial intelligence may support detection, workflow efficiency, malignancy risk reclassification, invasiveness assessment, and multimodal integration, but its value depends on external validation, calibration, implementation, and prospective evidence of management benefit. Mechanistic studies of adenocarcinoma spectrum subsolid nodules have implicated the involvement of early oncogenic signaling, genomic instability, immune escape, stromal and vascular remodeling, and adaptive survival pathways. Translational models can support mechanistic and procedural research, but do not replicate real-world nodule management in patients. Overall, care for pulmonary nodules should be risk-adapted, longitudinal, multidisciplinary, and patient-centered.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184231","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":"Nedd4L-mediated stabilization of morphogenetic protein receptor 2 in lung fibroblasts confers protection against pulmonary fibrosis.","authors":"Qinmao Ye, Baoyinna Baoyinna, Nargis Shaheen, Sarah J Taleb, Gitae Choi, Narasimham L Parinandi, Yingze Zhang, Daniel J Kass, Mauricio Rojas, Qin Ma, Chengyu Gao, Jeffrey Horowitz, Jing Zhao, Yutong Zhao","doi":"10.1038/s41392-026-02786-2","DOIUrl":"10.1038/s41392-026-02786-2","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease that advances over time and is ultimately life-threatening. Despite advances in antifibrotic therapies, disease progression remains largely unavoidable, highlighting the necessity for advancing mechanistic research and identifying new therapeutic options. Bone morphogenetic protein receptor 2 (BMPR2) is a key receptor for BMP signaling and exerts potent antifibrotic role in lung fibrosis; however, the molecular mechanisms regulating BMPR2 protein stability in fibrotic lungs remain poorly understood. In this study, we identify that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated protein 4-like (Nedd4L) as a critical regulator of BMPR2 stability in lung fibroblasts. BMPR2 levels are markedly reduced in lung fibroblasts derived from patients with IPF and in lung tissues from experimental lung fibrosis models. Mechanically, elevated lipid peroxidation in fibrotic lungs induces K48-linked ubiquitination of BMPR2, leading to its degradation and attenuation of BMPs-induced Smad1/5 phosphorylation. Notably, Nedd4L overexpression counteracts lipid peroxidation-induced BMPR2 degradation and promotes BMPs/BMPR2 signaling by shifting BMPR2 ubiquitination toward a stabilizing K63-linked polyubiquitination in lung fibroblasts. We further show that Nedd4L is regulated through threonine phosphorylated by Raf1 kinase in response to increased lipid peroxidation. In vivo, fibroblast-Nedd4L-deficient mice exacerbates experimental lung fibrosis, which is significantly alleviated by BMPR2 overexpression. Collectively, our findings reveal a previously unrecoganized regulatory mechanism of BMPR2 degradation in fibrotic lungs and indicate that stabilizing BMPR2 in lung fibroblasts may represent a promising approach for the treatment of lung fibrosis.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169281","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}