Journal of Translational Medicine最新文献

{"title":"Macrophage derived VEGF regulates macrophage senescence to inhibit radiation-induced dermatitis.","authors":"Rishi Man Chugh, Pooja Gupta-Saraf, Payel Bhanja, Subhrajit Saha","doi":"10.1186/s12967-025-07016-x","DOIUrl":"10.1186/s12967-025-07016-x","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are essential for maintaining tissue homeostasis and accelerating the repair processes; however, their functionality can be severely compromised in pathological conditions such as radiation-induced dermatitis. In this study we analyzed the role of macrophage derived Vascular Endothelial Growth Factor (VEGF) on regulation of macrophage senescence and its role on radiation-induced skin damage.</p><p><strong>Methods: </strong>We used bone marrow-derived macrophages (BMMɸ) isolated from Csf1r-iCre; VEGF^fl/fl (VEGF-null) and wild-type (WT) mice. Macrophages were exposed to oxidative and genotoxic stress using H₂O₂, doxorubicin, and radiation exposure to evaluate senescence. Senescence was assessed via SA-β-Gal staining and expression of senescence-related genes. Additionally, VEGF receptor inhibition in WT macrophages was performed to determine the role of VEGF/VEGFR signaling in senescence regulation. Phagocytosis and migration assays were conducted to evaluate functional differences. For in vivo analysis, WT and Csf1r-iCre; VEGF^fl/fl mice were exposed to radiation, and skin toxicity, histological changes, and senescence markers in skin macrophages were assessed.</p><p><strong>Results: </strong>VEGF-null macrophages showed increased sensitivity to senescence, with elevated SA-β-Gal staining and upregulated senescence-associated gene expression. WT macrophages treated with a VEGF receptor inhibitor displayed increased senescence-associated markers expression, highlighting the importance of VEGF/VEGF-R signaling in preventing macrophage senescence-like phenotypes. Additionally, VEGF-null macrophages have reduced phagocytic and migratory abilities. Our in vivo study using Csf1r-iCre; VEGF^fl/fl mice showed more severe radiation-induced dermatitis, including increased skin toxicity, hyperkeratosis, and elevated senescence-associated markers in skin macrophages compared to WT controls.</p><p><strong>Conclusions: </strong>Absence of macrophage-derived VEGF leads to heightened macrophage dysfunction and exacerbates radiation-induced dermatitis. Targeting VEGF signaling may serve as a potential therapeutic strategy to mitigate radiation-related skin toxicity and improve patient outcomes during radiation therapy.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"985"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic variations in glioma stem cells: regulatory mechanisms and implications for therapeutic strategies.","authors":"Guofeng Tian, Yifu Song, Yaochuan Zhang, Liang Kan, Ana Hou, Sheng Han","doi":"10.1186/s12967-025-07034-9","DOIUrl":"10.1186/s12967-025-07034-9","url":null,"abstract":"<p><p>Glioma represents the most prevalent primary tumors of the central nervous system, originating from glial cells. Cancer stem cells have the ability to extensively proliferate, self-renew, and form colonies, which contribute to tumorigenesis. Studies have found a population of cells within glioblastoma exhibiting characteristics similar to those of cancer cells, termed glioma stem cells (GSCs). GSCs have two distinct phenotypes: mesenchymal subtype (MES) and proneural subtype (PN). Despite the vital role of these subtypes in glioma biology, there is a significant lack of comprehensive reviews focusing on the regulatory mechanisms underlying each phenotype.This review integrates emerging insights into the regulatory mechanisms underlying GSCs plasticity, with dedicated analysis of novel pathways governing PN and MES phenotypes and their dynamic transition. By examining these critical elements, we aim to contribute to the development of novel therapeutic strategies in the ongoing fight against gliomas.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"984"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caspase-9 activates β-catenin signaling to promote pulmonary fibrosis.","authors":"Juan Wang, Bei Qing, Linguo Gu, Hongzuo Chen, Ying Chen, Yaling Tang, Zhenglian Ge, Rui Hu, Yunchang Yuan, Zhenkun Xia","doi":"10.1186/s12967-025-07020-1","DOIUrl":"10.1186/s12967-025-07020-1","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary fibrosis (PF) is a progressive interstitial lung disease marked by extracellular matrix accumulation and epithelial damage, with limited therapeutic options. Alveolar epithelial cell apoptosis is a key pathological hallmark of PF, but the upstream regulators driving this process remain unclear. Caspase-9, a central initiator of the intrinsic apoptotic pathway, has been implicated in fibrotic diseases across multiple organs. However, its role in lung fibrosis and its molecular interactions are not fully elucidated.</p><p><strong>Methods: </strong>Caspase-9 expression was analyzed in human PF lung tissues, bleomycin (BLM)-induced mouse models, and TGF-β1-treated MLE-12 alveolar epithelial cells. Functional studies included pharmacological inhibition, siRNA knockdown, and overexpression of Caspase-9. Fibrosis and apoptosis were assessed using Western blot, qPCR, immunohistochemistry, TUNEL, and electron microscopy. Interaction with β-catenin was examined via co-localization, modulation, and rescue experiments.</p><p><strong>Results: </strong>Caspase-9 and cleaved-Caspase-9 were significantly upregulated in fibrotic lungs and TGF-β1-stimulated epithelial cells. Caspase-9 inhibition reduced collagen deposition, improved lung architecture, and suppressed pro-fibrotic markers in mice. In MLE-12 cells, Caspase-9 knockdown attenuated TGF-β1-induced apoptosis, restored E-cadherin, and downregulated fibrotic genes. Conversely, Caspase-9 overexpression aggravated fibrosis and apoptosis. Mechanistically, Caspase-9 interacted with β-catenin, enhanced its nuclear accumulation, and promoted downstream fibrotic signaling. β-catenin silencing reversed Caspase-9-induced fibrosis, while β-catenin activation nullified the protective effects of Caspase-9 inhibition both in vitro and in vivo. These results identify a functional Caspase-9/β-catenin axis in PF progression.</p><p><strong>Conclusions: </strong>Caspase-9 drives pulmonary fibrosis by promoting epithelial apoptosis and activating β-catenin signaling. Targeting the Caspase-9/β-catenin axis may offer a promising therapeutic strategy for PF.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"986"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of big challenge of cancer screening in various societies: what is debatable and significant?","authors":"Maryam Ghaemi-Amiri, Mostafa Mostafazadeh-Bora","doi":"10.1186/s12967-025-07002-3","DOIUrl":"10.1186/s12967-025-07002-3","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"976"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum TSP-1 is a useful biomarker in severity assessment and the diagnosis of osteoarthritis.","authors":"Xianda Che, Chengming Zhang, Yuhao Zhuo, Huanya Li, Xueting Ding, Gaige Wu, Fuyang Cao, Guohao Zhang, Yukun Yin, Li Guo, Pengcui Li, Lu Li, Xiaochun Wei","doi":"10.1186/s12967-025-07022-z","DOIUrl":"10.1186/s12967-025-07022-z","url":null,"abstract":"<p><strong>Objective: </strong>Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation. Thrombospondin-1 (TSP-1) is a secreted trimeric glycoprotein with multiple functions. It can bind to various cell-surface receptors and is downregulated in OA chondrocytes. However, the utility of TSP-1 as a biomarker for OA remains unclear. Therefore, we aimed to investigate the association between serum TSP-1 concentration and knee OA.</p><p><strong>Design: </strong>We quantified serum TSP-1 concentrations in mice with post-traumatic OA (PTOA) and age-dependent OA (ADOA) using enzyme-linked immunosorbent assay (ELISA). We statistically analyzed the correlation between TSP-1 concentration and OA severity. Additionally, we generated cartilage-specific TSP-1 knockout mice and assessed TSP-1 concentration in the serum. Finally, we measured the concentrations of TSP-1 in the serum and synovial fluid of patients with OA and conducted statistical analyses to evaluate the correlation between TSP-1 concentration and Outerbridge grading. ROC curve analysis was used to determine the diagnostic value of TSP-1 for OA.</p><p><strong>Results: </strong>Serum TSP-1 concentration was reduced in wild-type mice with PTOA or ADOA and negatively correlated with OA severity. In cartilage-specific TSP-1 knockout mice, serum TSP-1 levels were decreased. In patients with OA, serum and synovial fluid TSP-1 levels were reduced and negatively correlated with OA severity. These findings suggest that TSP-1 may serve as a potential biomarker for the diagnosis of OA.</p><p><strong>Conclusion: </strong>Serum TSP-1 concentration is associated with OA severity in both mice and humans and may serve as a useful diagnostic biomarker for OA.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"987"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLC16A3 as an immunosuppressive Kupffer cell marker predicts poor prognosis in HBV-positive hepatocellular carcinoma.","authors":"Jingcheng Zhang, Yuyan Pan, Zhengqi Zhao, Bochen Chen, Wei Fan, Sicheng Zhao, Yuanlin Lv, Tao Jiang","doi":"10.1186/s12967-025-06861-0","DOIUrl":"10.1186/s12967-025-06861-0","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is one of the malignant tumors that currently pose a significant threat to human health, with infection by hepatitis B virus (HBV) being a critical risk factor for the development of HCC. It is critical to identify potential molecular targets affecting HBV-positive HCC patients.</p><p><strong>Methods: </strong>In this study, we comprehensively utilized single-cell sequencing and external transcriptome sequencing databases to further analyze the mechanism of SLC16A3's influence on liver cancer and its microenvironment under different HBV status. Immunohistochemical staining in our clinical cohort was used to analyze the expression difference and influence of SLC16A3 in HCC. At the same time, we confirmed the direct effects of SLC16A3 on HCC cells with different HBV status through cell line experiments.</p><p><strong>Results: </strong>Compared with normal tissues, SLC16A3 expression is up-regulated in HBV-positive HCC patients, and the up-regulation amplitude is greater than that in HBV-negative HCC patients, and it is associated with poor prognosis. The validation was performed on several external validation data sets and external validation queues. Multi-omics analysis showed that SLC16A3 expression is related to the specific differentiation of the immune microenvironment, especially Kupfer cells, which can mediate the emergence of the inhibitory immune microenvironment and indirectly lead to poor prognosis. SLC16A3 can directly mediate the proliferation of HBV-positive liver cancer cell lines in vitro.</p><p><strong>Conclusion: </strong>Our study found that SLC16A3 is closely related to HBV status and liver cancer, and it has a significant marker for the prognosis of HBV-positive liver cancer. SLC16A3 is associated with abnormal metabolic pattern and immune regulation of Kupffer cells, and can directly affect HBV-positive hepatocellular carcinoma cell lines.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"988"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outbreak dates of virus could be predicted by their protein sequence.","authors":"Peijun Zuo, Longlong Zuo, Zhihong Li, Xiaotong Zhou, Yanping Yu, Qinqing Wu, Yixiao Niu, Qiaocheng Chang, A Bakr M Rabie, Paul Lam, Liping Li","doi":"10.1186/s12967-025-07051-8","DOIUrl":"10.1186/s12967-025-07051-8","url":null,"abstract":"<p><strong>Introduction: </strong>Since 1970, monkey-pox, the last outbreak of smallpox, coronavirus was outbreak in the world for more than 50 years. To find if the outbreak dates could be predicted by their one-dimension protein sequence, the mathematical model was needed to establish between them.</p><p><strong>Methods: </strong>(A) collecting the outbreak dates of monkey-pox, smallpox, and coronavirus, determine the outbreak time interval between the pathogen strain and the reference strain SARS-CoV-2 D614, z. (B) detecting the one-dimension antigenic amino acid sequence of the pathogen strain to determine the super-antigens. (C) calculating the super-antigen precision, determining the increase amount in antigen precision between the pathogen strain and the reference strain, x; y represents the number of tryptophan (W) in the super-antigen. (D) Determine the correlation among the outbreak time interval z, the increase amount in antigen precision, x, and the number of W the super-antigen contains, y.</p><p><strong>Results: </strong>The regression equation is z = 13.762x²- 109.376x- 63.290y + 221.197, with a correlation coefficient of R = 1.0000000. After statistical testing, the probability of class I errors occurring is P = 0.008.</p><p><strong>Conclusions: </strong>The method can predict the outbreak dates by one-dimension protein sequence, such as monkey-pox, smallpox, and coronavirus.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"980"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAFs promote immune evasion in gastric cancer through histone lactylation-mediated suppression of NCAPG ubiquitination.","authors":"Sheng Zhou, Linmei Xiao, Li Hu, Fei Zuo, Yuanhang Wang, Bojian Fei, Jialin Dai, Xinyi Zhou","doi":"10.1186/s12967-025-07013-0","DOIUrl":"10.1186/s12967-025-07013-0","url":null,"abstract":"<p><strong>Background: </strong>Cancer-associated fibroblasts (CAFs) can facilitate tumor progression through multiple approaches. Research indicates that CAFs in various tumors exhibit robust lactate metabolism, ultimately becoming the primary source of lactate in the tumor microenvironment. Emerging evidence has established that CAFs could orchestrate gastric cancer (GC) immune evasion. However, the potential role of CAFs-derived lactate in immunotherapy remains elusive.</p><p><strong>Methods: </strong>In our research, CUT&Tag and transcriptome sequencing were employed to detect the target gene of histone lactylation. Co-immunoprecipitation, mass spectrometry analysis, and molecular docking, were utilized to explore the interactions between proteins. We performed cellular, animal, and organoid experiments to verify the mechanism.</p><p><strong>Results: </strong>We found that lactate secreted by CAFs was elevated, facilitating the lactylation of H3K18 in GC cells. As a target of H3K18la, ASPM played crucial roles in regulating the GC progression by promoting resistance to anti-PD-1. Mechanistically, ASPM promoted the transport of NCAPG from the nucleus to the cytoplasm by directly binding to it and then enhanced the deubiquitination of NCAPG mediated by BUB3, thereby increasing the expression of NCAPG. Furthermore, NCAPG targeted the SRC/STAT3 pathway and elevated PD-L1 expression. In addition, Daturilin has been preliminarily identified as a small-molecule inhibitor targeting NCAPG.</p><p><strong>Conclusions: </strong>In conclusion, we have identified that CAFs-derived lactate promoted GC progression and clarified its mechanism, proposing the H3K18la-ASPM-NCAPG axis. Daturilin could enhance the therapeutic efficacy of anti-PD-1 treatment. This offers innovative perspectives on the complex role of CAFs in the TME and the influence of lactate on tumor progression.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"989"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implicates of PIP5K1α in asthma-related biological processes: insights into mechanisms and therapeutic potential.","authors":"Si-Jia Wang, Fuwen Yuan, Lei-Miao Yin","doi":"10.1186/s12967-025-06997-z","DOIUrl":"10.1186/s12967-025-06997-z","url":null,"abstract":"<p><p>PIP5K1α is a key member of the lipid kinase family, involved in several cellular processes including cell proliferation and differentiation, cytoskeletal remodeling, inositol-phospholipid signaling, intracellular vesicle transport, and protein secretion. Emerging evidence now highlights critical functions of PIP5K1α in asthma-related biological processes. In this review, we aim to consolidate existing literature on the involvement of PIP5K1α in asthma pathogenesis. We summarize PIP5K1α-related pathways that regulate airway immune homeostasis (regulating T cell/ILCs-mediated immune response, TLR4/MyD88/NF-κB signaling pathway, Let-7 miRNA biogenesis, and its regulatory modifications), airway hyper-responsiveness (modulating of calcium release, airway smooth muscle contractility, and epithelial barrier dysfunction), and airway remodeling (regulating cell migration, proliferation, epithelial remodeling, and cytoskeleton modulation) in asthma. Although clinically approved PIP5K1α inhibitors are currently unavailable, targeting this kinase present a compelling therapeutic strategy for asthma, requiring further research into develop effective treatments.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"978"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Butyric acid and valeric acid attenuate stress-induced ferroptosis and depressive-like behaviors by suppressing hippocampal neuroinflammation.","authors":"Xiaoying Ma, Weibo Shi, Zhen Wang, Shujin Li, Rufei Ma, Weihao Zhu, Lin Wu, Xiaowei Feng, Bin Cong, Yingmin Li","doi":"10.1186/s12967-025-06950-0","DOIUrl":"10.1186/s12967-025-06950-0","url":null,"abstract":"<p><strong>Background: </strong>Depression is closely associated with stress-induced hippocampal damage and dysfunction. Emerging evidence demonstrates that the gut microbiota and its metabolites, acting as probiotics or prebiotics, can modulate brain structure and function via the gut-brain axis, thereby offering therapeutic potential for ameliorating related neurological and psychiatric disorders. This study delves into the contribution of the gut microbiota and its metabolites to stress-induced ferroptosis of hippocampal neurons and the associated molecular pathways.</p><p><strong>Methods: </strong>This study used time-course stress paradigms combined with ferroptosis inhibitors to identify hippocampal neuronal ferroptosis. Fecal microbiota transplantation were conducted to analyze the role of gut microbiota in this process. Subsequently, 16 S rDNA sequencing and metabolomics techniques were applied to identify key gut microbiota and metabolites. Metabolites intervention were performed to examine their causal relationship with neuronal ferroptosis. Finally, we used histochemical and molecular assays to assess both intestinal and blood-brain barrier integrity as well as inflammation in peripheral blood and hippocampal tissue, along with GPR41/RhoA/Rock1 pathway changes, to preliminarily investigate the molecular mechanisms underlying stress-induced hippocampal neuronal ferroptosis.</p><p><strong>Results: </strong>We demonstrated that stress triggered hippocampal neuronal ferroptosis and subsequent depressive-like behaviors in mice. Fecal microbiota transplantation successfully replicated the ferroptosis phenotype. Butyric acid and valeric acid were identified as key metabolites significantly reduced in the serum of acutely and chronically stressed mice, respectively. Intervention with these metabolites markedly alleviated ferroptosis. Furthermore, valerate intervention increased hippocampal GPR41 expression and significantly suppressed the pro-inflammatory RhoA/Rock1 pathway in chronically stressed mice, thereby reducing neuroinflammation and ameliorating neuronal ferroptosis. However, butyrate intervention showed no significant effect on the GPR41/RhoA/Rock1 pathway.</p><p><strong>Conclusion: </strong>Stress induces ferroptosis in hippocampal neurons, where reduced abundance of short-chain fatty acid-producing bacteria plays a key role. Key metabolites butyric acid and valeric acid alleviate neuroinflammation to improve ferroptosis via the gut-brain axis in acute and chronic stress, respectively. Specifically, valeric acid exerts neuroprotective effect through the GPR41/RhoA/Rock1 pathway, whereas butyric acid-mediated protection likely operates through alternative mechanisms.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"974"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}