{"title":"Pro-inflammatory microglia-targeted peptide therapy ameliorates neonatal hypoxic-ischemic encephalopathy in mice.","authors":"Rika Zen, Shunichiro Tsuji, Tomoko Maeda, Makoto Urushitani, Takashi Murakami, Tomoya Terashima","doi":"10.1016/j.ymthe.2025.03.002","DOIUrl":"10.1016/j.ymthe.2025.03.002","url":null,"abstract":"<p><p>Neonatal hypoxic-ischemic encephalopathy is aggravated by intracerebral inflammation. As pro-inflammatory microglia in the brain become activated in this condition, we aimed to establish a novel peptide therapy for neonatal hypoxic-ischemic encephalopathy by investigating the therapeutic effects of pro-inflammatory microglial depletion. MG1 homing peptide, which selectively targets and binds pro-inflammatory microglia, was conjugated with the pro-apoptotic peptide <sub>D</sub>[KLAKLAK]<sub>2</sub> (KLA), creating MG1-KLA. After confirming that MG1-KLA selectively bound pro-inflammatory microglia and decreased cell viability by inducing apoptosis in a dose-dependent manner, the in vivo therapeutic effect of MG1-KLA was assessed following intracerebroventricular injection in hypoxic-ischemic encephalopathy model mice through histological, behavioral, and biochemical analyses. In these mice, MG1-KLA selectively bound to microglia and induced their apoptosis. Brain atrophy was significantly suppressed in the mice treated with MG1-KLA compared with non-treated mice. Additionally, motor function and locomotor hyperactivity were improved in mice treated with MG1-KLA compared with non-treated mice. Gene expression analysis further revealed that pro-inflammatory cytokine expression was downregulated in mice treated with MG1-KLA compared with non-treated mice. These findings suggest that novel MG1-KLA peptide therapy has high potential for treating neonatal patients with hypoxic-ischemic encephalopathy through the selective induction of apoptosis in pro-inflammatory microglia.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3177-3194"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586365","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":"Interaction between stromal cells and tumor cells promotes GCB-DLBCL cell survival via the CD40/RANK-KDM6B-NF-κB axis.","authors":"Dandan Liu, Haohao Zhang, Yiwang Zhang, Liping Xiao, Jingyao Wang, Shiyan Liao, Hongrui Chen, Huilian Wu, Yiming Hu, Yuhang Jiang, Qi Wang, Cuifeng Li, Pengfei Chen, Yu Zhan, Lingling Li, Ningxia Xie, Deji Ye, Donglin Sun, Yingyong Hou, Yufang Shi, Yongzhong Liu, Jiang Zhu, Wei Li, Chunkui Shao, Xiaoren Zhang","doi":"10.1016/j.ymthe.2025.03.025","DOIUrl":"10.1016/j.ymthe.2025.03.025","url":null,"abstract":"<p><p>The stromal cells as the main component of the tumor microenvironment in germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) probably is accountable for therapy resistance and relapse. To investigate the interaction between tumor cells and stromal cells, we established GCB-DLBCL patient-derived xenograft models to isolate primary tumor cells and coculture them with stromal cells. Additionally, we presented GCB-DLBCL cases with histopathologic confirmation and analyzed the online databases to explore the underlying mechanisms. We demonstrated that CD40 ligand (CD40L) expressed on stromal cells activated the CD40 pathway in GCB-DLBCL tumor cells, protecting tumor cells from apoptosis and up-regulating RANK ligand (RANKL). The RANKL expressed on tumor cells enhanced the expression of CD40L and BAFF in stromal cells, which in turn promoted tumor cells survival through activating NF-κB signaling. Significantly, the activation of CD40 pathway up-regulated KDM6B, a lysine-specific demethylase, and KDM6B further enhanced the transcription activity of NF-κB signaling, which has not been reported in B cells. Here, we provided compelling evidence that the interaction between stromal cells and tumor cells functions as a bona fide anti-apoptotic factor in GCB-DLBCL. This interaction mainly involves the CD40/RANK-KDM6B-NF-κB axis, which represents a promising therapeutic target for GCB-DLBCL.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3407-3422"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676679","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":"AAV-Sparcl1 promotes hair cell regeneration by increasing supporting cell plasticity.","authors":"Nianci Li, Fangzhi Tan, Liyan Zhang, Xiaoqiong Ding, Qiuhan Sun, Man Wang, Ziyu Zhang, Yicheng Lu, Yinyi Zhou, Xiaoyun Qian, Fanglei Ye, Jieyu Qi, Renjie Chai","doi":"10.1016/j.ymthe.2025.03.054","DOIUrl":"10.1016/j.ymthe.2025.03.054","url":null,"abstract":"<p><p>Sensorineural hearing deficiency caused by hair cell damage represents a prevalent sensory deficit disorder. In mammals, age-related reduction in plasticity of inner ear supporting cells (recognized as hair cell precursors) compromises their trans-differentiation capacity, resulting in impaired spontaneous hair cell regeneration post-injury. Therapeutic reprogramming of supporting cells to functionally replace damaged hair cells has emerged as a promising strategy for sensorineural hearing loss treatment. In this study, we demonstrate that the secretory protein Sparcl1 enhances supporting cell reprogramming and hair cell regeneration in both in vitro and in vivo models. Through the adeno-associated virus (AAV)-mediated overexpression system, we successfully achieved in vivo expansion of inner ear organoids accompanied by hair cell differentiation. RNA-seq analysis revealed that Sparcl1 overexpression stimulates supporting cell proliferation via follistatin (Fst) activation and extracellular matrix (ECM) remodeling. Notably, both AAV-ie-Sparcl1 delivery and recombinant Sparcl1 protein administration effectively induced supporting cell differentiation into hair cells in vivo. Collectively, our findings establish Sparcl1 as a potent positive regulator of hair cell regeneration and elucidate mechanisms by which secretory proteins regulate supporting cell plasticity.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3022-3035"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780666","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":"Combined AAV-mediated specific Gjb2 expression restores hearing in DFNB1 mouse models.","authors":"Qiuhan Sun, Fangzhi Tan, Liyan Zhang, Yicheng Lu, Hao Wei, Nianci Li, Lulu Jiang, Yinyi Zhou, Tian Chen, Ling Lu, Geng-Lin Li, Jieyu Qi, Shiming Yang, Renjie Chai","doi":"10.1016/j.ymthe.2025.03.029","DOIUrl":"10.1016/j.ymthe.2025.03.029","url":null,"abstract":"<p><p>Pathogenic mutations in the Gjb2 gene, encoding connexin 26, are the leading cause of autosomal recessive hereditary deafness. Gene therapy holds significant promise for treating this. Adeno-associated virus (AAV)-mediated therapeutic gene delivery has been shown to be safe and effective in restoring hearing in both animal models and human patients. However, Gjb2 gene therapy has been hindered by the limited specificity and efficiency of the available AAV vectors. In this study, we screened AAV serotypes and found that co-administration of AAV1 and AAV-ie could effectively target Gjb2-expressing cells. However, the ectopic Gjb2 expression in hair cells induced by these AAVs could cause ototoxicity, which was addressed by employing the specific promoter SCpro. Co-injection of AAV1 and AAV-ie carrying exogenous Gjb2 driven by SCpro effectively restored hearing function in Gjb2-deficient mice. Moreover, the combined AAV system can transduce the cochleae of Bama miniature pigs and AAV administration into the inner ear of cynomolgus monkeys did not impair hearing and showed negligible systemic toxicity, indicating the efficiency and safety of this gene therapy in large animals. Thus, this study provides a strategy for Gjb2 gene therapy and lays a foundation for future clinical applications.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3006-3021"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692715","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2025-06-25DOI: 10.1016/j.ymthe.2025.06.011
Francesco Di Meo
{"title":"Memory matters: T cell phenotype shapes CAR T cell fate.","authors":"Francesco Di Meo","doi":"10.1016/j.ymthe.2025.06.011","DOIUrl":"10.1016/j.ymthe.2025.06.011","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2975-2976"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506877","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":"Peeling back the layers of immunogenicity in CRISPR/Cas9-based genomic medicine.","authors":"Virpi Stigzelius,Anna Lina Cavallo,Rakesh Kantilal Chandode,Roberto Nitsch","doi":"10.1016/j.ymthe.2025.06.045","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.045","url":null,"abstract":"The CRISPR/Cas9 system is rewriting the treatment of genetic diseases, offering unprecedented potential for detrimental and previously untreatable diseases. As this technology advances towards wider utilization in clinical applications, the immunogenicity of Cas9 nuclease has emerged as a potential challenge for in vivo therapies. Immune recognition of CRISPR/Cas9 components can trigger both innate and adaptive responses. The complex interactions between Cas9, delivery vectors, and host immune responses play a crucial role in determining the safety and efficacy of CRISPR-based treatments. Recent advances in mitigating Cas9 immunogenicity include epitope engineering, optimized delivery systems, and nucleic acid modifications. These strategies, explored across various tissue contexts and delivery methods, show promise in enhancing the tolerability of CRISPR-based therapies. However, pre-existing immunity to Cas9 and the potential for long-term adaptive immune responses remain important considerations. Addressing these immunological challenges requires an integrated approach, combining insights from immunology with innovative engineering solutions. As the field progresses, overcoming Cas9 immunogenicity will be crucial for realizing the full therapeutic potential of the CRISPR/Cas9 system in diverse clinical applications.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"104 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547774","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}
Molecular TherapyPub Date : 2025-07-01DOI: 10.1016/j.ymthe.2025.06.035
Tomas S Aleman,Katherine E Uyhazi,Alejandro J Roman,Mariejel L Weber,Erin C O'Neil,Malgorzata Swider,Alexander Sumaroka,Katherine H Maguire,Elena M Aleman,Arlene J Santos,Rebecca J Kim,Kelsey M Parchinski,Andrew Billek,Makayla Fradin,William Chung,Paris Margaritis,Junwei Sun,Drew H Scoles,Vivian Wu,Alexandra V Garafalo,Ashwath Jayagopal,Ben Yerxa,Sarah Tuller,Albert M Maguire,Jean Bennett,Artur V Cideciyan
{"title":"Recovery of Cone-Mediated Vision in Lebercilin-Associated Severe Retinal Ciliopathy (LCA5) after Gene Therapy: One Year Results of a Phase Ib/IIa Trial.","authors":"Tomas S Aleman,Katherine E Uyhazi,Alejandro J Roman,Mariejel L Weber,Erin C O'Neil,Malgorzata Swider,Alexander Sumaroka,Katherine H Maguire,Elena M Aleman,Arlene J Santos,Rebecca J Kim,Kelsey M Parchinski,Andrew Billek,Makayla Fradin,William Chung,Paris Margaritis,Junwei Sun,Drew H Scoles,Vivian Wu,Alexandra V Garafalo,Ashwath Jayagopal,Ben Yerxa,Sarah Tuller,Albert M Maguire,Jean Bennett,Artur V Cideciyan","doi":"10.1016/j.ymthe.2025.06.035","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.035","url":null,"abstract":"We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated Leber congenital amaurosis (LCA5-LCA), a congenital blindness. The phase 1b/2a trial (NCT05616793) is a nonrandomized, single ascending, dose-escalation study. Three subjects with LCA5-LCA (ages 19, 26 and 34 years old) received uniocular subretinal injections of 1E10 vector genome per eye of OPGx-001. There were no serious adverse events related to OPGx-001 or the procedure. Retinal microstructure by SD-OCT showed no major changes in retinal lamination of the treated central retina compared to the contralateral control. Efficacy was detectable in these severely affected patients by subjective and objective methods at one-month post-treatment and persisted for at least 12 months. Chromatic full-field stimulus testing showed improvements in cone-mediated vision averaging ∼1 log10 unit. Objective pupillometry confirmed perceptual results. Improvements were associated with better performance on a virtual reality orientation and mobility test. Visual acuity returned to baseline or improved in the treated eyes of all participants. The favorable safety profile and efficacy outcomes pave the path for enrolling milder phenotypes with careful dose escalation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533476","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":"Galectin-4 potentiates CD8+ T cell immunity by enhancing MHC-I expression on dendritic cells: Therapeutic implications for cancer and viral infection.","authors":"In-Gu Lee,Jeonghyeon Lee,Hyeong-Rae Kim,Younghyun Lim,Hye-Won Yu,Tae-Hyung Kim,Bumsuk Hahm,Hyun Ah Kang,So-Hee Hong,Young-Jin Seo","doi":"10.1016/j.ymthe.2025.06.040","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.040","url":null,"abstract":"Galectin-4 (Gal-4), a member of the β-galactoside-binding galectin family, plays a role in various physiological processes, including tumor progression and intestinal disorders. However, its contribution to adaptive immunity remains poorly understood. In this study, Gal-4 is identified as a critical factor for effective generation of CD8+ T cell responses against tumors and viral infections. Gal-4-deficient mice exhibit significantly enhanced tumor growth in syngeneic mouse cancer models, attributed to impaired CD8+ T cell responses. Similarly, antiviral CD8+ T cell responses against lymphocytic choriomeningitis virus (LCMV) are profoundly diminished in Gal-4-deficient mice. This is not due to CD8+ T cell-intrinsic defects but instead linked to decreased surface expression of antigen-MHC-I complexes on dendritic cells. Building on these findings, the therapeutic potential of Gal-4 is investigated. Administration of Gal-4 enhances the efficacy of cancer vaccines and PD-1 blockade cancer therapy to improve outcomes in tumor-bearing mice. Additionally, systemic administration of Gal-4 markedly amplifies antiviral CD8+ T cell responses against LCMV. Collectively, these results underscore the pivotal role of Gal-4 in modulating CD8+ T cell immunity and highlight its promise as a therapeutic target for the development of novel immunotherapeutics against cancer and viral diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521335","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}
Molecular TherapyPub Date : 2025-06-30DOI: 10.1016/j.ymthe.2025.06.038
Yi Wang,Jinghua Liu,Sha Zhu,Shiliang Hu,Xiupeng Chen,Elisabet Mandon,Ngoc Tam Tran,Songbo Zhang,Yangran Qi,Hong Ma,Ran He,Yu Cao,Qin Su,Thomas L Gallagher,Zixiu Ii,Chan Zhou,Philip W L Tai,Guangping Gao,Jun Xie
{"title":"miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression.","authors":"Yi Wang,Jinghua Liu,Sha Zhu,Shiliang Hu,Xiupeng Chen,Elisabet Mandon,Ngoc Tam Tran,Songbo Zhang,Yangran Qi,Hong Ma,Ran He,Yu Cao,Qin Su,Thomas L Gallagher,Zixiu Ii,Chan Zhou,Philip W L Tai,Guangping Gao,Jun Xie","doi":"10.1016/j.ymthe.2025.06.038","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.038","url":null,"abstract":"Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the FDA-approved treatment for APAP overdose, but there is a growing interest in microRNAs as potential therapeutic agents. We delivered miR-375 ectopically via a liver-tropic adeno-associated virus serotype 8 (AAV8) and demonstrated its potent protection in a murine model of APAP overdose-induced ALF. Slc16a2, Cyb5b, and Acsl5 were identified as critical targets acting synergistically to mitigate toxicity. Liver transcriptome revealed that miR-375 overexpression or silencing of the targets of miR-375 increased Gstm3 expression in mice. AAV8-mediated Gstm3 expression protects against APAP-ALF, and the protection was further enhanced by disrupting the expression of Cyp2e1. Additionally, CYP2E1 and GSS, which contribute to APAP detoxification, were down- and upregulated by miR-375, respectively. These findings suggest that miR-375 prevents APAP-ALF by orchestrating the expression of pharmacogenes and enhancing glutathione synthesis. We conclude that miR-375 and its targets are promising therapeutic targets for APAP-ALF.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"467 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533477","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":"Circulating urobilinogen contributes to Inflammation, Intestinal Permeability and corticosteroid non-response in Severe Alcohol-associated Hepatitis.","authors":"Manisha Yadav,Abhishak Gupta,Babu Mathew,Gaurav Tripathi,Nishu Dalal,Neha Sharma,Pushpa Yadav,Gaurav Yadav,Rita Singh,Vasundhra Bindal,Rimsha Saif,Sanju Yadav,Nupur Sharma,Sushmita Pandey,Sadam H Bhat,Ravinder Singh,Jitender Kumar,Manish Kushwaha,Tahseen Khan,Narendra Kumar Sharma,Ashima Bhaskar,Ved Prakash Dwivedi,Anil Kumar,Niraj Kumar,Dinesh Mani Tripathi,Nirupama Trehanpati,Anupama Kumara,Shvetank Sharma,Shiv Kumar Sarin,Jaswinder Singh Maras","doi":"10.1016/j.ymthe.2025.06.041","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.041","url":null,"abstract":"Severe alcohol-associated hepatitis (SAH) is a life-threatening condition with high mortality rates and poor response to prednisolone therapy. Identifying reliable early predictors of therapy response and survival is critical. Plasma metabolomics was conducted on 70 SAH patients (50 responders, 20 non-responders) to identify biomarkers for non-response and early mortality. These findings were validated in a cohort of 153 patients and an independent cohort of 245 using high resolution mass spectrometry, machine learning, and severity indices. Temporal metabolic changes indicated interactions between the host and microbiome, with a focus on inflammation and intestinal permeability. Plasma metabolomics revealed that non-responders had significantly higher urobilinogen levels (3.6-fold change). Additionally, a decrease in alpha/beta diversity and temporal metabolic inactivity characterized non-responders. Plasma urobilinogen levels predicted non-response (AUC>0.97) and identified non-survivors (AUC=0.94) with a threshold of >0.07 mg/ml. Urobilinogen levels correlated with bacterial peptides belonging to Firmicutes and Proteobacteria, neutrophil activation, oxidative stress, and pro-inflammatory cytokine production. These changes contributed to non-response by increasing glucocorticoid receptor β expression and compromising intestinal permeability. Fecal microbiota transplantation decreased urobilinogen levels by reducing bilirubin reductase gene-containing microbiota. Plasma urobilinogen >0.07 mg/ml could predict early mortality, and modulation of the gut microbiome may improve outcomes in SAH patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"65 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521363","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}