Molecular Medicine最新文献

{"title":"The post-transcriptional regulatory RNA-binding protein PTBP1 functions as an inhibitor in hepatic stellate cell activation and liver fibrosis.","authors":"Feifan Xu, Yajun Zhou","doi":"10.1186/s10020-026-01541-1","DOIUrl":"10.1186/s10020-026-01541-1","url":null,"abstract":"<p><strong>Background: </strong>Hepatic stellate cell (HSC) activation is the key step in liver fibrogenesis characterized by excessive extracellular matrix (ECM) accumulation, which is based on fibrogenic factors-induced changes in gene expression in HSCs. The post-transcriptional gene-expression regulation plays a crucial role in regulation of gene expression by controlling mRNA fate through RNA binding proteins (RBPs), RBPs are essentially involved in the process of HSC activation and liver fibrogenesis. Since the activated HSCs possess the characteristics of neuron and the roles of multifunctional polypyrimidine tract binding protein 1 (PTBP1), a key RBP in inhibiting neuron differentiation, in HSC activation and liver fibrosis are elusive, this research aimed to investigate the effects of PTBP1 on HSC activation and liver fibrosis.</p><p><strong>Methods: </strong>The study employed RNA sequencing, targeted over-expression of Ptbp1, Ptbp1 gene-knockdown mice, different mouse model of liver fibrosis, and liver samples from clinical patients.</p><p><strong>Results: </strong>Ptbp1 silencing in HSCs in vitro led to an increase in the expression of many pro-fibrotic genes, including at least the most potent fibrogenic factors, fibrogenic factor receptors, signal transducer, and ECM, but caused a decrease in the expression of pro-apoptotic genes and transcriptional factor Srebp1c, a key one to inhibiting HSC activation. Ptbp1 knockdown in mouse upregulated the expression of pro-fibrotic genes and enhanced HSC activation as well as liver fibrosis. Targeted over-expression of Ptbp1 in HSCs in the model of liver fibrosis further confirmed the effects of PTBP1 on the pro- and anti-fibrotic gene expression in HSCs, HSC activation, and liver fibrosis. Ptbp1 could bind to Srebp1c mRNA, thus inhibiting its degradation. PTBP1 also blocked PI3K/Akt pathway in HSCs. Its levels were reduced in the activated HSCs in livers from mice and clinical patients.</p><p><strong>Conclusion: </strong>This research demonstrated a previously unrecognized inhibitory effect of the multifunctional PTBP1 on HSC activation and liver fibrogenesis and the underlying mechanisms were involved in PTBP1 regulation of the important pro- or anti-fibrotic genes. Given that PTBP1 targeted lots of important pro- and anti-fibrotic genes, PTBP1 may serve as a potential therapeutic strategy for treatment of liver fibrosis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339311","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":"Oncolytic adenovirus co-expressing IL-12 and shVEGF potentiates immune checkpoint blockade for treatment of renal cell carcinoma: in vitro, organ-on-a-chip, and in vivo evaluation.","authors":"Joongwon Choi, Chae-Ok Yun, Sejung Maeng, Yunlim Kim, Eunyoung Park, Ji Yi, Se Young Choi, In Ho Chang, A-Rum Yoon","doi":"10.1186/s10020-026-01535-z","DOIUrl":"10.1186/s10020-026-01535-z","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) has been known as highly malignant and resistant to standard therapy due to its immunosuppressive tumor microenvironment and aberrant VEGF-mediated angiogenesis. To overcome these therapeutic limitations, here we assessed the therapeutic efficacy of an oncolytic adenovirus (oAd) co-expressing Interleukin-12 (IL-12) and a short hairpin RNA against VEGF (shVEGF) in combination with immune checkpoint inhibitors (ICIs). The oAd/IL12/shVEGF induced RCC-specific cancer cell death in vitro and 3D bioprinted model, leading to greater anti-tumor effect compared with oAd-GMCSF. Furthermore, it potentiates anti-tumor efficacy in RCC orthotopic tumor model. The potent antitumor effect induced by combination of oAd/IL12/shVEGF with anti-PD1 was due to CD4 + or CD8 + T cell- or NK cell-mediated antitumor immune response and effective inhibition of tumor-associated neovascularization. Collectively, oAd/IL12/shVEGF can be a potent strategy to overcome current limitations in conventional RCC therapy by converting the cold tumor microenvironment to an inflamed state to sensitize refractory tumors to ICIs.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339366","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":"CEMIP1 and TACSTD2 as circulating mRNA biomarkers for early detection and tumor burden assessment in colorectal neoplasia.","authors":"Katerina Balounova, Anusha Uttarilli, Josef Horak, Veronika Makajevova, Ladislav Sojka, Jaromir Simsa, Jan Bruha, Vaclav Liska, Saba Selvi, Vlasta Korenkova, Sona Vodenkova, Jiri Jungwirth, Peter Macinga, Tomas Hucl, Jan Kral, Michaela Schneiderova, Anna Valickova, Veronika Vymetalkova","doi":"10.1186/s10020-026-01537-x","DOIUrl":"https://doi.org/10.1186/s10020-026-01537-x","url":null,"abstract":"<p><strong>Background: </strong>Early and minimally invasive detection of colorectal neoplasia remains a major challenge in cancer prevention. Current blood-based screening approaches lack sufficient sensitivity for early-stage lesions and advanced adenomas, highlighting the need for novel circulating biomarkers.</p><p><strong>Methods: </strong>This study employs an integrative multi-phase approach combining whole-transcriptome RNA sequencing (RNA-seq) [patients with colorectal adenoma (CRA), n = 16; patients with colorectal cancer (CRC), n = 7; healthy controls, n = 10] with two-step RT-qPCR validation in tissue and plasma samples (CRA, n = 48; CRC, n = 48 for each TNM stage I-III and n = 42 for TNM IV; healthy controls n = 51). The study design encompasses discovery, validation, and liquid biopsy phases, enabling systematic prioritization of candidate genes across independent cohorts. This strategy was used to identify circulating mRNA biomarkers for early detection and monitoring of CRA (including both advanced and non-advanced adenomas) and CRC across the adenoma-carcinoma sequence, including pre- and post-operative plasma collections.</p><p><strong>Results: </strong>RNA-seq analyses identified over 4,000 differentially expressed genes in CRA and CRC tissues compared to matched adjacent mucosa and colonic mucosa from healthy controls. Subsequent validation confirmed a consistent upregulation of several candidates, with TACSTD2 and CEMIP1 emerging as the most robust and biologically relevant. Both genes showed concordant expression patterns between tissue and plasma, supporting their detectability in liquid biopsy. TACSTD2 was markedly upregulated in CRA tissue and plasma, indicating its utility as an early biomarker of neoplastic transformation. Importantly, its elevation in premalignant lesions suggests a potential future contribution to biomarker-based risk stratification and screening settings. CEMIP1 mRNA levels were significantly elevated in CRC tissue and plasma and declined following tumor resection, reflecting a strong association with tumor burden.</p><p><strong>Conclusions: </strong>By integrating tissue and liquid biopsy analyses, this study identifies TACSTD2 and CEMIP1 as promising circulating mRNA biomarkers for early detection and post-surgical monitoring of colorectal neoplasia. Their complementary biological roles across different stages of tumorigenesis support their combined use in a multiplex diagnostic approach. These findings support the clinical translation of mRNA-based biomarkers into non-invasive diagnostic tools with the potential to enhance CRC screening and personalized patient management.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148331228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hematopoietic stem and progenitor cells derived platelet lysate promotes diabetic wound healing.","authors":"Ying Zhang, Lingna Wang, Zhongyuan Zheng, Haitao Yuan, Xiankun Yin, Chenyu Zhang, Jiaqing Liu, Chao Li, Qun Ma, Long Zhang, Fangfang Zhu, Wenhui Wang, Lu Tie","doi":"10.1186/s10020-026-01520-6","DOIUrl":"10.1186/s10020-026-01520-6","url":null,"abstract":"<p><strong>Background: </strong>Diabetic wounds represent an escalating clinical challenge driven by the rising global prevalence of diabetes and the lack of effective treatments. Platelets serve as natural reservoirs of diverse growth factors, holding considerable promise for promoting tissue regeneration and wound repair. However, current platelet-derived therapies are constrained by donor dependence, protocol variability, and inconsistent product quality.</p><p><strong>Methods: </strong>This study established an efficient in vitro protocol for generating functional platelets from human hematopoietic stem and progenitor cells (HSPCs). These regenerative platelets were subsequently lysed to produce induced human platelet lysate (ihPL). The contents of key growth factors in ihPL and human peripheral blood platelet lysate (hPL) were compared by enzyme-linked immunosorbent assay (ELISA). We established diabetic mice wound model to evaluate the therapeutic efficacy of ihPL on wound healing. Furthermore, in vitro experiments assessed the effects of ihPL on dermal fibroblasts proliferation, migration, and collagen synthesis. Transcriptome sequencing and Western blot (WB) were employed to elucidate the underlying signaling pathways.</p><p><strong>Results: </strong>HSPCs differentiation into megakaryocytes exceeded 80%, with a subsequent platelet production efficiency of 38.3% ± 5.35%. ELISA revealed that the concentrations of fibroblast growth factor (140.1 ± 0.986 vs. 1.0 ± 0.008) and vascular endothelial growth factor (12.74 ± 5.280 vs. 1.0 ± 0.276) were significantly elevated in ihPL compared with hPL. In diabetic mice, ihPL (89.44% ± 9.83%), hPL (73.60% ± 12.21%), and epidermal growth factor (EGF, 59.72% ± 12.87%) significantly accelerated wound closure compared with the vehicle control group (43.53% ± 16.09%) at day 14 (P < 0.05). Notably, ihPL demonstrated superior efficacy relative to both hPL and EGF (P < 0.05). Histological analysis and Optical coherence tomography angiography confirmed enhanced extracellular matrix deposition and angiogenesis with ihPL versus vehicle control. Furthermore, ihPL significantly promoted dermal fibroblasts proliferation, migration, and collagen synthesis in vitro. Transcriptome analyses indicated activation of multiple tissue regeneration-associated signaling pathways and WB further confirmed the upregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway representing a potential underlying mechanism.</p><p><strong>Conclusion: </strong>This study establishes a standardized, donor-independent, and immunologically safer cell-based therapeutic strategy for diabetic wound management, with considerable potential for clinical translation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148318143","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":"Finerenone mitigates acute alcoholic myocardial injury by modulating inflammatory signaling, oxidative stress, and mitochondrial function.","authors":"Ching-Han Liu, Tian-Huei Chu, Shih-Ming Yang, Yi-Chen Wang, Wen-Chin Lee, Yi-Chen Chang, Yao-Chang Chen, Yi-Jen Chen, Cheng-Chieh Fang, Zhi-Hong Wen, Chien-Wei Feng, Hao-Ming Wu, Po-Tseng Lee, Nan-Chieh Huang, Shih-Chung Huang","doi":"10.1186/s10020-026-01532-2","DOIUrl":"10.1186/s10020-026-01532-2","url":null,"abstract":"<p><strong>Background and purpose: </strong>Alcoholic cardiomyopathy (ACM) is a serious complication of chronic and acute alcohol abuse that can progress to heart failure (HF). Currently, no curative drug exists for ACM, and heart transplantation remains the only definitive option. Although mineralocorticoid receptor (MR) antagonists (MRAs) are a cornerstone of HF management, their role in ethanol cardiotoxicity remains poorly defined. Because ethanol elevates aldosterone levels, targeting the aldosterone/MR axis may represent a promising therapeutic strategy. This study investigated the effects of finerenone, a next-generation non-steroidal MRA, in both in vitro and in vivo models of acute alcoholic myocardial injury.</p><p><strong>Methods: </strong>H9c2 cardiomyocytes were exposed to ethanol with or without finerenone, and cell viability, apoptosis, mitochondrial dynamics, and proinflammatory signaling were assessed to evaluate cytoprotective effects. In vivo, a murine acute alcoholic myocardial injury model was generated by three days of ethanol exposure with concurrent finerenone administration. Circulating myocardial injury marker CK-MB was measured, and myocardial tissue was analyzed for MR/aldosterone levels, apoptosis, inflammation, macrophage infiltration, and mitochondrial fission/fusion dynamics.</p><p><strong>Results: </strong>Finerenone attenuated ethanol-induced MR upregulation, apoptosis, mitochondrial fragmentation, and pro-inflammatory signaling in H9c2 cardiomyocytes. In mice, finerenone further reduced the ethanol-induced increase in serum CK-MB and attenuated ethanol-induced myocardial cell death and damage. Moreover, ethanol-induced myocardial inflammation, oxidative stress, and mitochondrial dysfunction were further reduced in this mouse model of ethanol cardiotoxicity following finerenone administration. Together, the non-steroidal MRA finerenone may attenuate acute ethanol-induced cardiotoxicity by regulating inflammatory pathways, oxidative stress, and mitochondrial function.</p><p><strong>Conclusions and implications: </strong>Overall, these findings support the conclusion that the next-generation MRA finerenone attenuates acute ethanol-induced myocardial cell death, inflammation, oxidative stress, and mitochondrial dysfunction in vitro and in vivo. Finerenone may act as a novel protective agent against acute alcoholic myocardial injury in the future, but further clinical evidence is required to support this preclinical finding.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295426","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":"Gut dysbiosis modulates hyperoxia-induced bronchopulmonary dysplasia by promoting EMT through activating TLR4/NF-κB pathway.","authors":"Yaqin Yan, Shuling Liang, Sen Li, Shunv Xie, Xiaohui Wang, Huayan Zhang","doi":"10.1186/s10020-026-01529-x","DOIUrl":"10.1186/s10020-026-01529-x","url":null,"abstract":"<p><strong>Background: </strong>Bronchopulmonary dysplasia (BPD) is a major cause of morbidity and mortality in premature infants. Although gut microbial dysbiosis is implicated in BPD pathogenesis, the underlying mechanisms are poorly defined. This study aims to elucidate the specific pathway through which gut dysbiosis drives BPD pathology and to identify potential therapeutic targets.</p><p><strong>Methods: </strong>The experimental BPD model was established by hyperoxia (FiO₂ 85%) in neonatal mice from postnatal days 1 to 14. Pulmonary alveolarization and inflammation were analyzed at postnatal day 15. The modulatory role of gut microbiota was assessed using antibiotic-induced dysbiosis and fecal microbiota transplantation (FMT) from normoxic mice. Gut microbiome analysis was performed using 16S rRNA gene sequencing. The specific signaling pathway was investigated using a pharmacological inhibitor of TLR4. Furthermore, the molecular mechanisms were investigated through western blotting, real-time quantitative PCR, ELISA, and immunofluorescence.</p><p><strong>Results: </strong>Hyperoxia exposure induced impaired alveolarization, disrupted gut barrier integrity, and gut dysbiosis. These pathological changes were accompanied by elevated pulmonary inflammation, potent activation of the TLR4/NF-κB pathway, and upregulation of epithelial-mesenchymal transition (EMT) associated markers. These changes were exacerbated by early postnatal antibiotic administration, whereas FMT from normoxic mice rescued these phenotypes, restored gut barrier function, suppressed TLR4/NF-κB signaling, and reversed EMT progression. Notably, pharmacological inhibition of TLR4 mirrored the protective effects of FMT, effectively attenuating hyperoxia-induced lung injury and EMT.</p><p><strong>Conclusions: </strong>Our findings establish a mechanistic link for the gut-lung axis in BPD, demonstrating that gut dysbiosis is a critical modulator of lung development impairment and pathological EMT via activation of the TLR4/NF-κB pathway.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265411","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":"Genetic variants in IGF2BP family genes are associated with glioma risk in Chinese children.","authors":"Yuling Su, Yuxiang Liao, Li Yuan, Linqian Wang, Jiabin Liu, Haixia Zhou, Tianyou Wang, Jing He","doi":"10.1186/s10020-026-01527-z","DOIUrl":"10.1186/s10020-026-01527-z","url":null,"abstract":"<p><strong>Background: </strong>Glioma is a highly prevalent malignant tumor of the central nervous system in children and is driven by complex genetic and environmental factors. IGF2BP family genes (IGF2BP1, IGF2BP2, and IGF2BP3) encode critical RNA epigenetic \"readers\" that participate in posttranscriptional gene regulation and modulate various cellular processes. However, the contributions of these gene variants to glioma risk remain unclear.</p><p><strong>Methods: </strong>A multicenter case-control study was conducted, enrolling 360 patients with glioma and 547 cancer-free controls. Genotyping of 11 potentially functional polymorphisms within IGF2BP family genes was performed using the TaqMan assay. Unconditional logistic regression models were employed to estimate odds ratios and 95% confidence intervals. Furthermore, expression quantitative trait loci (eQTL) and The Cancer Genome Atlas (TCGA) clinical database analyses were conducted to investigate the potential regulatory mechanisms and clinical significance of the identified variants.</p><p><strong>Results: </strong>We found that the IGF2BP1 rs2270575 polymorphism was significantly associated with a decreased risk of glioma. Conversely, the IGF2BP2 rs17289925 and rs7646419 polymorphisms were linked to increased glioma risk. Stratification and cumulative effect analyses revealed that harboring multiple risk genotypes of IGF2BP1 or IGF2BP2 substantially increased glioma susceptibility. This cumulative risk was especially notable among males, younger children (< 60 months), and patients diagnosed with early-stage (I + II) tumors. Additionally, eQTL and TCGA analyses revealed that the rs2270575 and rs7646419 alleles correlated significantly with altered mRNA expression levels of CALCOCO2 and AC099661.1 (ENSG00000286086), respectively, which further correlated with favorable molecular subtypes (IDH mutation status) and WHO tumor grades.</p><p><strong>Conclusion: </strong>Genetic polymorphisms within IGF2BP family genes significantly modulate pediatric glioma susceptibility and have cumulative, subtype-specific, and age-dependent effects; thus, these genes may serve as promising noninvasive biomarkers for early risk stratification of childhood glioma.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258908","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":"β-Adrenergic receptors as immunomodulators in T cells: mechanisms of neuroimmune crosstalk and pathophysiological implications.","authors":"Junyan Yao, Suli Zhang, Fei Sun, Mingyang Chen, Huirong Liu","doi":"10.1186/s10020-026-01526-0","DOIUrl":"10.1186/s10020-026-01526-0","url":null,"abstract":"<p><p>Regulation of T cell function by the sympathetic nervous system via β-adrenergic receptors is a pivotal research focus in neuroimmunology, with most studies centered on β₂-adrenergic receptors. However, the roles of other subtypes remain unclear. This review systematically summarizes differential expression and signaling of β₂- and β₁-adrenergic receptors across T cell subsets. While β₂-adrenergic receptor bidirectionally modulates immune responsiveness through classical or non-classical pathways, β₁-adrenergic receptor is predominantly expressed in regulatory and exhausted T cells, exerting immunosuppression via the cAMP-CREM axis. Furthermore, this review examines the pathophysiological roles of β-adrenergic receptor signaling in the tumor immune microenvironment, autoimmune diseases, infections and cardiovascular diseases, highlighting β₁-adrenergic receptor as a candidate immune checkpoint. Ultimately, elucidating the subtype-specific mechanisms of β-adrenergic signaling provides a critical framework for understanding immune dysregulation and highlights the potential of targeting these pathways to restore immune homeostasis in various pathological contexts.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258898","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":"Formyl peptide receptor 1 agonism selectively suppresses mitochondria-driven neutrophil extracellular trap formation while preserving antibacterial immunity.","authors":"Emil Bečka, Letícia Hudecová, Patrik Bertovič, Karolína Bíla, Ľudmila Podracká, Peter Celec, Michal Pastorek","doi":"10.1186/s10020-026-01522-4","DOIUrl":"10.1186/s10020-026-01522-4","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial damage-associated molecular patterns (mtDAMPs) released after trauma can trigger neutrophil extracellular trap (NET) formation, potentially worsening tissue injury and increasing susceptibility to secondary infection. However, the mechanisms driving mitochondria-induced NETosis and whether this response can be selectively modulated without impairing antibacterial defense remain unclear.</p><p><strong>Methods: </strong>We investigated the mechanisms of mitochondria-induced NET formation using in vitro, in vivo models and ex vivo, using trauma patient plasma. Neutrophils were exposed to intact mitochondria or mitochondrial components, and the roles of Toll-like receptor 9 (TLR9), formyl peptide receptor 1 (FPR1), PAD4, NOX2, p38α, and STAT6 were assessed. Effect of the synthetic FPR1 agonist FPRA14 on NET formation and antibacterial neutrophil functions was tested in double hit in vivo model of peritoneal mitochondria injection followed by S. aureus pneumonia.</p><p><strong>Results: </strong>Intact mitochondria induced NET formation through coordinated activation of both TLR9 and FPR1, with dependence on PAD4, NOX2, and p38α signaling. Mitochondrial protein integrity was important for this response, likely by protecting mtDNA from degradation and enabling TLR9 activation. While insufficient to drive NETosis alone, FPR1 activation showed a concentration- and time-dependent modulatory effect: low-level activation promoted NETosis, whereas stronger or pre-exposure-induced signaling suppressed it through receptor desensitization. FPR1 agonist FPRA14 reduced mitochondria-driven NET formation in vitro and in a double hit murine model while preserving neutrophil antibacterial functions, including NET formation, phagocytosis, ROS generation, bacterial killing, and infection control. p38α acted as a positive regulator, whereas STAT6 functioned as a negative regulator of NET formation.</p><p><strong>Discussion: </strong>These findings identify FPR1 as a key regulator of pathological mitochondria-driven NETosis and suggest that selective FPR1 receptor desensitization may suppress excessive sterile inflammation without compromising host defense. This work extends current understanding of mtDAMP signaling in neutrophils and supports prophylactic FPR1 agonism as a potential strategy for limiting inflammatory tissue damage after trauma or surgery.</p><p><strong>Conclusion: </strong>Mitochondria-induced NETosis depends on TLR9/FPR1 signaling and can be reduced by FPR1 agonism without compromising antibacterial immunity. FPRA14 may represent a strategy to limit harmful sterile inflammation after trauma or surgery.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252505","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":"The role of Dymeclin in chronic unpredictable mild stress-induced depression: maintaining the Golgi apparatus structure and regulating NLRP3 inflammasome activation.","authors":"Longfei Du, Zifan Ding, Lei Sun, Ye Qin, Huiling Sun, Yuqin Pan, Shukui Wang","doi":"10.1186/s10020-026-01524-2","DOIUrl":"10.1186/s10020-026-01524-2","url":null,"abstract":"<p><p>The Golgi apparatus plays a key role in innate immune signaling, but its exact role in depression-related neuroinflammation remains unclear. The role of Dymeclin (DYM), a Golgi structural protein, in stress-related psychiatric disorders needs further clarification. This study aims to investigate whether DYM participates in the development of chronic stress-induced depression by regulating Golgi function. A mouse depression model was developed with chronic unpredictable mild stress (CUMS), followed by a rescue experiment using stereotactic injection of DYM-overexpressing lentiviruses into the hippocampus. Depression-associated behaviors, hippocampal metabolites, Golgi apparatus function, and inflammatory markers were examined using mass spectrometry, immunofluorescence, electron microscopy, and immunoprecipitation techniques. Overexpression of DYM mitigated depressive-like behaviors induced by CUMS in mice. Additionally, it enhanced the structural integrity of the Golgi apparatus, suppressed NLRP3 inflammasome activation, reduced levels of central and peripheral inflammatory factors, and partially ameliorated hippocampal metabolic disturbances. In vitro experiments further confirmed that DYM overexpression inhibited LPS-induced NLRP3 upregulation and inflammatory factor release in microglia. This study reveals that chronic stress causes depressive-like behaviors by reducing hippocampal DYM expression, leading to Golgi dysfunction and triggering NLRP3 inflammasome-related neuroinflammation and metabolic issues.This finding broadens the traditional framework of depression research, which has primarily focused on neurons and monoamine neurotransmitters, by underscoring the pivotal role of Golgi organelle homeostasis in mediating the interactions among stress, neuro-immune, and metabolic processes. Our research indicates that targeting the DYM/Golgi pathway could offer new treatment strategies and a theoretical foundation for reducing depression-related neuroinflammation and metabolic issues. Drugs targeting the structural stability of the Golgi apparatus may serve as potential candidates for novel antidepressants in the future.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252443","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}