Advanced SciencePub Date : 2025-07-20DOI: 10.1002/advs.202510778
Qingdeng Fan, Min Wang, Jie Lin, Ya Huang, Jing Yang, Jiaoyang Zhu, Bin Ren, Li Sun, Zongheng Li, Aochi Liu, Wei Xiong, Zhenni Wei, Lin Huang, Chenggong Yan, Ge Wen, Zhao Chen, Xiaoyuan Chen, Zheyu Shen
{"title":"A Mesoporous Calcium Peroxide Nanocuboid with High Tumor Accumulation Across Biological Barriers for High Efficacy Tumor Therapy.","authors":"Qingdeng Fan, Min Wang, Jie Lin, Ya Huang, Jing Yang, Jiaoyang Zhu, Bin Ren, Li Sun, Zongheng Li, Aochi Liu, Wei Xiong, Zhenni Wei, Lin Huang, Chenggong Yan, Ge Wen, Zhao Chen, Xiaoyuan Chen, Zheyu Shen","doi":"10.1002/advs.202510778","DOIUrl":"https://doi.org/10.1002/advs.202510778","url":null,"abstract":"<p><p>The common problem of tumor therapy based on nanoparticles is the limited efficacy due to the blockage of tumor accumulation by biological barriers. To enhance the drug delivery of nanoparticles across biological barriers and augment their tumor accumulation, herein, a mesoporous calcium peroxide nanocuboid (MCPNC) is developed via a facile hydrolysis-precipitation method, which can be utilized for high efficacy tumor therapy by promoting a positive feedback loop of Fenton reaction. The biodistribution results demonstrate that MCPNC exhibits higher accumulation in various tissues than calcium peroxide nanosphere (CPNS). Ferroheme (FH) and exceedingly small magnetic iron oxide nanoparticle (IO) loaded MCPNC is modified with hyaluronic acid (HA), forming MCPNC-FH-IO@HA. Under acidic tumor microenvironment (TME), Fe<sup>3+/2+</sup>, H<sub>2</sub>O<sub>2</sub> and Ca<sup>2+</sup> can be released from MCPNC-FH-IO@HA. The reactive oxygen species (ROS) generation through Fenton reaction can disrupt mitochondrial membranes, which accelerates the unbalance of Ca<sup>2+</sup> mitochondrial homeostasis. The loss of mitochondrial membrane potential activates mitochondrial autophagy, which results in the release of Fe<sup>3+/2+</sup> in tumor mitochondria. The released Fe<sup>3+/2+</sup> can further produce more and more ROS via the Fenton reaction, which establishes the positive feedback loop of the Fenton reaction. Both in vitro and in vivo results demonstrate that MCPNC-FH-IO@HA exhibits remarkable antitumor efficacy, superior MRI performance, and favorable biosafety.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e10778"},"PeriodicalIF":14.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advanced SciencePub Date : 2025-07-20DOI: 10.1002/advs.202413288
Chuandong Lang, Xiangyu Mu, Kun Chen, Xinwen Wang, Yuluo Rong, Jia Wang, Zongcheng Yang, Chi Yin, Yuhu Dai, Jun Xiao, Wenzhi Zhang
{"title":"Epigenetic Activation of CCDC183-AS1 Promotes Osteoclastogenesis and Prostate Cancer Bone Metastasis Through the FUBP1/LIGHT Axis.","authors":"Chuandong Lang, Xiangyu Mu, Kun Chen, Xinwen Wang, Yuluo Rong, Jia Wang, Zongcheng Yang, Chi Yin, Yuhu Dai, Jun Xiao, Wenzhi Zhang","doi":"10.1002/advs.202413288","DOIUrl":"https://doi.org/10.1002/advs.202413288","url":null,"abstract":"<p><p>Bone metastasis (BM) is a major contributor to poor prognosis of prostate cancer (PCa); however, the underlying mechanisms of PCa BM remain poorly understood. A better understanding of these processes may provide critical insights for developing effective preventive and therapeutic strategies for PCa BM. In this study, significant upregulation of CCDC183-AS1 in PCa BM is identified, which is associated with disease progression. CCDC183-AS1 overexpression enhanced the ability of PCa cells to spread to the bone by inducing osteoclastogenesis and aiding in the creation of a BM niche. Mechanistically, CCDC183-AS1 interacted with FUBP1 and enhanced its stability by inhibiting JTV-1-mediated ubiquitination and degradation of FUBP1, which promoted the transcription of TNFSF14 (LIGHT). Copy number gain-induced upregulation of KDM5C epigenetically enhanced CCDC183-AS1 expression by recruiting TET1 to its promoter and promoting DNA demethylation. Significantly, the administration of the selective FUBP1 inhibitor, FUBP1-IN-1, is shown to effectively suppress CCDC183-AS1-induced PCa BM. These results shed light on the involvement of CCDC183-AS1 in enhancing osteoclastogenesis and the underlying mechanism in facilitating PCa BM, offering a potential avenue for therapeutic interventions.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e13288"},"PeriodicalIF":14.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advanced SciencePub Date : 2025-07-20DOI: 10.1002/advs.202509419
Peifen Lu, Hongxiu Yuan, Gang Wang, Tao Cheng, Lie Li, Yixi Dong, Runyu Zhao, Xuerui Zhang, Jianwei Jiao, Jin Jiao
{"title":"A Charge-Adhesive Targeted DNA Gel Bandage for the Precision Treatment of Inflammatory Bowel Disease.","authors":"Peifen Lu, Hongxiu Yuan, Gang Wang, Tao Cheng, Lie Li, Yixi Dong, Runyu Zhao, Xuerui Zhang, Jianwei Jiao, Jin Jiao","doi":"10.1002/advs.202509419","DOIUrl":"https://doi.org/10.1002/advs.202509419","url":null,"abstract":"<p><p>The exacerbation and recurrence of inflammatory bowel disease (IBD) are closely related to the overactivation of the immune system and the destruction of the intestinal mucosa. Current small-molecule and biopharmaceutical therapies for IBD are often limited by off-target effects, low bioavailability, and poor treatment outcomes, leading to systemic side effects and severe complications. To address these challenges, DNA gel bandage (DNAgb) designed to block immune cell homing and inhibit inflammatory responses are proposed. DNAgb is a negatively charged \"sticky excipient\" formed by a rolling circle amplification production hydrogel and an integrin α4 aptamer (ApITGA4) -guided tetrahedral DNA nanostructure. This unique design enables dual-specific localization to inflamed mucosa through electrostatic interactions and ApITGA4-mediated affinity targeting. Our studies have demonstrated that DNAgb exhibits precise targeting, superior stability, and robust anti-inflammatory efficacy. It effectively inhibits activation of the NF-κB signaling pathway, decreases the secretion of inflammatory factors and reshapes the immune microenvironment. Transcriptome analysis further reveals the underlying mechanism of DNAgb in IBD therapy, highlighting its role in inflammation repression. Therefore, DNAgb provides a promising strategy for local therapeutic agents that effectively inhibit the inflammatory response and provides a new and effective choice for the treatment of IBD.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e09419"},"PeriodicalIF":14.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advanced SciencePub Date : 2025-07-20DOI: 10.1002/advs.202509800
Wei Qin, Sheng-Jia Lin, Yu Zhang, Kevin Huang, Cassidy Petree, Kevin Boyd, Pratishtha Varshney, Gaurav K Varshney
{"title":"Rationally Designed TadA-Derived Cytosine Editors Enable Context-Independent Zebrafish Genome Editing.","authors":"Wei Qin, Sheng-Jia Lin, Yu Zhang, Kevin Huang, Cassidy Petree, Kevin Boyd, Pratishtha Varshney, Gaurav K Varshney","doi":"10.1002/advs.202509800","DOIUrl":"10.1002/advs.202509800","url":null,"abstract":"<p><p>CRISPR base editors are crucial for precise genome manipulation. Existing APOBEC-based cytosine base editors (CBEs), while powerful, exhibit indels and sequence context limitations, and editing CC and GC motifs is challenging and inefficient. To address these challenges, existing tRNA adenine deaminase (TadA)-derived CBEs are evaluated in zebrafish, and a series of zTadCBE variants is developed that demonstrate high editing efficiency, minimized off-target effects, and an expanded targeting range compared to existing tools. The approach integrates beneficial mutations from TadA-based adenine base editors (ABEs) with SpRYCas9n-enhanced protospacer-adjacent motif (PAM) compatibility. The expanded window zTadCBE variants enable the targeting of cytosines at a broader range of nucleotide positions relative to the PAM sequence, further enhancing the versatility of this tool. Using zTadCBEs, four zebrafish disease models affecting the auditory, nervous, metabolic, and muscular systems are generated directly in the F0 generation-models that cannot be efficiently produced using earlier CBE tools. Together, zTadCBE variants provide a robust and flexible toolkit for efficient and precise C-to-T base editing in zebrafish, facilitating rapid in vivo functional assessment of genetic variants.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e09800"},"PeriodicalIF":14.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advanced SciencePub Date : 2025-07-20DOI: 10.1002/advs.202505592
Vishal Chandra, Justin Garland, Rajani Rai, Donghua Zhao, Charuksha Walgama, Sadagopan Krishnan, Andrew T Long, Tongzu Liu, Laura Adhikari, Doris M Benbrook
{"title":"Mortalin and PINK1/Parkin-Mediated Mitophagy Represent Ovarian Cancer-Selective Targets for Drug Development.","authors":"Vishal Chandra, Justin Garland, Rajani Rai, Donghua Zhao, Charuksha Walgama, Sadagopan Krishnan, Andrew T Long, Tongzu Liu, Laura Adhikari, Doris M Benbrook","doi":"10.1002/advs.202505592","DOIUrl":"https://doi.org/10.1002/advs.202505592","url":null,"abstract":"<p><p>Mortalin is an essential chaperone for the import of nuclear-encoded proteins into mitochondria and is elevated in ovarian cancer in association with poor patient prognosis. The investigational new drug, SHetA2, interacts with mortalin releasing its client proteins. In this study, interactions of SHetA2 moieties and mortalin substrate binding domain (SBD) amino acids are demonstrated by surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) to occur at low micromolar SHetA2 concentrations that selectively kill cancer cells over noncancerous cells. In both ovarian cancer and noncancerous cells SHetA2 reduces: mitochondria import of mortalin, degradation of mortalin's mitochondrial localization sequence (MLS), mortalin/inositol 1,4,5-trisphosphate receptors complexes and oxidative phosphorylation. In cancer cells only, SHetA2 reduces calcium levels, mitochondrial length and fusion proteins, while inducing autophagy and PTEN-induced kinase 1 (PINK1)/PARKIN-mediated mitophagy. Noncancerous cells exhibit increased mitochondrial branch length in response to SHetA2 and a low level of inducible autophagy that is resistant to SHetA2. Inhibition of autophagosome-lysosome fusion reduces, or increases, SHetA2 cytotoxicity in ovarian cancer or noncancerous cells, respectively. SHetA2 inhibits mortalin and growth, and induces mitophagy in ovarian cancer xenografts and increases survival post-surgical tumor removal. In conclusion, SHetA2 binds directly to mortalin's SBD and causes distinct responses in ovarian cancer and noncancerous cells.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e05592"},"PeriodicalIF":14.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.","authors":"Shuoting Zhou, Xi Xiong, Jialong Hou, Qi Duan, Yi Zheng, Tao Jiang, Jiani Huang, Haijun He, Jiaxue Xu, Keke Chen, Wenwen Wang, Jinlai Cai, Jingjing Qian, Huijun Chen, Weihong Song, XinShi Wang, Chenglong Xie","doi":"10.1002/advs.202408503","DOIUrl":"https://doi.org/10.1002/advs.202408503","url":null,"abstract":"<p><p>Serving as a pivotal hub for cellular metabolism and intracellular signaling, the mitochondrion has emerged as a crucial organelle whose dysfunction is linked to many human diseases, including neurodegenerative disorders, particularly Parkinson's disease (PD). However, whether mitochondrial quality control (MQC) can be targeted for therapeutic interventions remains uncertain. This study uses clinical samples, molecular biology techniques, pharmacological interventions, and genetic approaches to investigate the significance of NAD+ levels in cross-species models of PD. These results reveal that treatment of rotenone-incubated cells with NAD+ boosters (such as NMN, siCD38, and NAT) increases UPR<sup>mt</sup>/mitophagy-related MQC, reduces pro-inflammatory cytokine expression, inhibits apoptosis, and strengthen redox reactions. In vivo, NMN supplementation inhibits motor deficit and forestalls the neuropathological phenotypes of MPTP-induced PD mice, which are required for the atf4-related mitochondrial UPR pathway. Notably, bulk omics signatures and metabolomic profiling analyses of the striatum reveal NMN-induced transcriptional changes in genes and proteins involved in mitochondrial homeostasis. Thus, these findings demonstrate that the accelerated pathology in PD models is probably mediated by impaired MQC and that bolstering cellular NAD+ levels alleviates mitochondrial proteotoxic stress and mitigate PD phenotypes.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e08503"},"PeriodicalIF":14.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"High-Performance, Strain-Stable Electromagnetic Shielding Materials Enabled by Magnetic Elastic Fiber Networks Pinning Liquid Metal.","authors":"Qi Zhang, Yuanzhao Wu, Xilai Bao, Shengbin Li, Xueheng Zhuang, Zidong He, Jinyun Liu, Wuxu Zhang, Shiying Li, Feng Xu, Chuibin Zeng, Chao Hu, Qikui Man, Jie Shang, Yiwei Liu, Run-Wei Li","doi":"10.1002/advs.202510078","DOIUrl":"https://doi.org/10.1002/advs.202510078","url":null,"abstract":"<p><p>Stretchable electromagnetic interference (EMI) shielding materials are critical for the reliability of wearable electronic devices in complex electromagnetic environments. However, achieving compatibility between ultra-thinness, high shielding efficiency (SE), and excellent dynamic stability remains a major challenge in this field. Here, an ultrathin elastic EMI shielding film (TPU/Fe-LM) is developed by leveraging the magnetoelectric synergy effect and a pinning-interlocking mechanism between ferromagnetic elastic nanofiber networks and the embedded liquid metal (LM), achieving high EMI SE and excellent strain stability. The ultrathin film, with a thickness of 85 µm, exhibits an average EMI SE exceeding 70 dB across a broad frequency range of 0.1 MHz to 40 GHz, with only a 2.59% variation under 100% tensile strain. This superb EMI SE per unit thickness (SSE = 1225 dB mm<sup>-1</sup> @ 100% strain) ranks among the highest reported for stretchable EMI shielding films, highlighting the exceptional application potential. As a proof of concept, the EMI shielding film is integrated into a stretchable capacitive strain sensor for dynamic and static force sensing, achieving a 50-fold enhancement in angle resolution for robotic motion monitoring. This research paves the way for stretchable EMI shielding materials and offers valuable guidance for enhancing electromagnetic protection in wearable electronics.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e10078"},"PeriodicalIF":14.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advances in Medical Devices for Augmented Acupuncture Therapy.","authors":"Ruisi Cai, Chenyi Yu, Xinyi Luo, Ningyu Xu, Jicheng Yu, Xiao Ye, Yuqi Zhang, Zhen Gu","doi":"10.1002/advs.202505318","DOIUrl":"https://doi.org/10.1002/advs.202505318","url":null,"abstract":"<p><p>Acupuncture, as a traditional medicine applied worldwide, is considered an effective treatment for numerous chronic diseases. Many researches have explored the biological mechanisms of acupuncture, including the skin-neuro-immune axis and inflammation-immune modulation. However, traditional acupuncture faces several limitations, such as its complex operation, the wide variety of acupoint combinations, long treatment durations, and susceptibility to individual differences between the practitioner and the patient. These challenges highlight the urgent need for intelligent medical devices that enable more precise and efficient modern acupuncture treatment. In response to this, this manuscript introduces engineered acupuncture needles (EANs) using techniques such as macroscopic mechanical etching, microscopic surface modification, and biomedical nanotechnology. These modified needles enhance acupuncture treatment by incorporating drug delivery, electrical stimulation, and thermal stimulation technologies. Here we provide an overview of recent advancements in EANs in terms of materials, fabrication methods, engineering technologies, acupoints, as well as disease models. The relevant bottlenecks and future prospects of their development are also discussed.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e05318"},"PeriodicalIF":14.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advanced SciencePub Date : 2025-07-18DOI: 10.1002/advs.202503659
Zhengyan Wang, Zihan Li, Lei Wang, Haitao Zhang, Xiaoshan Yang, Lili Bao, Geng Dou, Lili Ren, Yajing Fu, Lan Li, Shengkai Gong, Yang Zhou, Feng Ding, Lu Yu, Haotian Luo, Yao Liu, Fuyang Zhang, Hui Yu, Siying Liu, Xueming Liu, Fulan Wei, Shiyu Liu
{"title":"Cellular Adaptation to Mechanical Stress Emerges via Cell Shrinkage Triggered by Nonlinear Calcium Elevation.","authors":"Zhengyan Wang, Zihan Li, Lei Wang, Haitao Zhang, Xiaoshan Yang, Lili Bao, Geng Dou, Lili Ren, Yajing Fu, Lan Li, Shengkai Gong, Yang Zhou, Feng Ding, Lu Yu, Haotian Luo, Yao Liu, Fuyang Zhang, Hui Yu, Siying Liu, Xueming Liu, Fulan Wei, Shiyu Liu","doi":"10.1002/advs.202503659","DOIUrl":"https://doi.org/10.1002/advs.202503659","url":null,"abstract":"<p><p>Organisms constantly encounter unpredictable environmental perturbations, necessitating adaptation to maintain homeostasis. However, the fundamental principles by which organisms identify specific cues and transition to an adaptive state remain unclear. Here, using a mouse mechanical ventilation model and a cell stretch model, it is found that the cellular adaptation to mechanical stress can be induced by applying low amplitude stretches to cells, and demonstrate that the adaptation emerges once a defined stretch threshold is reached. This adaptive state is marked by transient cell shrinkage and reduced membrane tension. Mechanistically, guided by a mathematical model of intracellular Ca<sup>2+</sup> dynamics, it is found that when stretch reaches a critical amplitude, it induces Ca<sup>2+</sup>-dependent positive feedback, leading to nonlinear Ca<sup>2+</sup> elevation. This activates scramblase Anoctamin-6, promoting extracellular vesicle-mediated membrane cholesterol efflux. The reduction in membrane cholesterol subsequently activates volume-regulated anion channels, leading to cell shrinkage and the establishment of mechanical adaptation. These findings reveal a threshold-dependent mechanism for mechanical adaptation emergence, and propose a promising strategy to develop targeted interventions in mechanical stress-related disorders.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e03659"},"PeriodicalIF":14.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advanced SciencePub Date : 2025-07-18DOI: 10.1002/advs.202501408
Tao Huang, Shijun Chen, Ke Ding, Liyan Yuan, Weiqi Lv, Kechen Chen, Yuchen Liu, Dongzhao Ma, Xin Zhang, Xiaobo Wang, Guanzheng Luo, Bin Yang, Ying Lin, Zhili Rong
{"title":"METTL3/ALKBH5-Mediated N6-Methyladenosine Modification Drives Macrophage M1 Polarization via the SLC15A3-TASL-IRF5 Signaling Axis in Psoriasis.","authors":"Tao Huang, Shijun Chen, Ke Ding, Liyan Yuan, Weiqi Lv, Kechen Chen, Yuchen Liu, Dongzhao Ma, Xin Zhang, Xiaobo Wang, Guanzheng Luo, Bin Yang, Ying Lin, Zhili Rong","doi":"10.1002/advs.202501408","DOIUrl":"https://doi.org/10.1002/advs.202501408","url":null,"abstract":"<p><p>Impaired N6-methyladenosine (m<sup>6</sup>A) modification has been implicated in regulating various inflammatory diseases, but its role in psoriasis remains unclear. Here, m<sup>6</sup>A modification and its methyltransferase METTL3 are revealed to be upregulated in psoriatic macrophages, while the demethylase ALKBH5 is downregulated. Conditional knockout of Mettl3 in macrophages alleviated psoriasis-like symptoms in mice, whereas knockout of Alkbh5 exacerbated them. Both in vivo and in vitro, Mettl3 deficiency inhibited IMQ-induced M1 macrophage polarization, while Alkbh5 deficiency promoted M1 polarization. The regulation of macrophage polarization by m<sup>6</sup>A is likely mediated by targeting Slc15a3. SLC15A3 enhances the recruitment of TASL, a recently identified endolysosomal IRF5 adaptor, which functions similarly to the IRF3 adaptors STING and MAVS at the endoplasmic reticulum (ER) and mitochondria, respectively, to augment IRF5 signaling via SLC15A4. The findings underscore the critical role of m<sup>6</sup>A RNA modification in psoriasis pathogenesis and unveil a novel regulatory mechanism of TASL-IRF5 signaling through m<sup>6</sup>A modification, suggesting potential new therapeutic targets for psoriasis treatment.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e01408"},"PeriodicalIF":14.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}