Hermann-Georg Holzhütter, Christian A Hudert, Nikolaus Berndt
{"title":"Patient-specific effects of metformin on the hepatic metabolism in adolescents with metabolic dysfunction-associated steatotic liver disease (MASLD).","authors":"Hermann-Georg Holzhütter, Christian A Hudert, Nikolaus Berndt","doi":"10.1007/s00109-025-02551-y","DOIUrl":"https://doi.org/10.1007/s00109-025-02551-y","url":null,"abstract":"<p><p>Metformin is a commonly prescribed antidiabetic drug that inhibits hepatic glucose production (HGP). Recent studies examining the use of metformin for the treatment of children with metabolic dysfunction-associated steatotic liver disease (MASLD) showed controversial results. To evaluate the patient-specific impact of metformin on hepatic glucose, lipid, amino acid, and energy metabolism in a cohort of 70 paediatric patients with biopsy-proven MASH. We parametrized our mathematical model HEPATOKIN1 of liver metabolism with patient-specific proteomics data of liver enzyme abundances and simulated metformin-induced diurnal changes of a large panel of metabolic functions. On average, a single dose (250 mg) of metformin reduced diurnal HGP by 19%. Based on a Z-score of 1, 15% of patients were classified as low responders or high responders. During elevated metformin plasma levels within four after metformin ingestion, energy metabolism, cytosolic and mitochondrial redox potential, urea synthesis and ketone body synthesis were reduced by 10-30%, but averaged over 24 h, these metabolic side effects were not significant. In particular, there was no significant impact of metformin on hepatic fat storage. Baseline lactate and insulin activity at 90 min after glucose challenge (OGTT) correlated significantly with the reduction in HGP and may serve as predictors of effective therapy. On a daily average, metformin selectively affects hepatic glucose production, glycogen storage and lactate uptake, while numerous other metabolic functions are significantly altered only for several hours after administration of the drug. Our method provides a patient-specific analysis of the potential effects of metformin therapy on central hepatic metabolism and may therefore help guide the physician's therapeutic decision.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The role of innate immunity triggered by HPV infection in promoting cervical lesions.","authors":"Kaiyu Fu, Xin Yang, Mengpei Zhang, Rutie Yin","doi":"10.1007/s00109-025-02553-w","DOIUrl":"https://doi.org/10.1007/s00109-025-02553-w","url":null,"abstract":"<p><p>Innate immunity is the immune system that organisms possess from birth. It is primarily responsible for the rapid, nonspecific recognition of pathogens when they invade, activating the host's immune response to eliminate. Cervical cancer is one of the most well-known tumors caused by human papillomavirus (HPV) infection. As the first line of defense against pathogens, innate immunity plays a crucial role in the response to HPV invasion, and there has been significant research in this area in recent years. The findings suggest that innate immune responses not only contribute to the clearance of HPV but may also facilitate the spread of the virus and the carcinogenic transformation of cervical epithelial cells. In this review, we comprehensively examine the activation of innate immune responses during HPV infection, the mechanisms by which HPV evades these immune defenses, and the role of innate immunity in promoting cervical intraepithelial neoplasia. Additionally, we explore the characteristics of innate immune responses within the tumor microenvironment of cervical cancer. Furthermore, we summarize recent advances in understanding the various mechanisms by which innate immune responses can be activated, with a focus on potential therapeutic implications. By reviewing the latest research, this article aims to provide valuable insights and stimulate further investigation into the role of innate immunity in HPV-associated cervical lesions, potentially leading to more effective strategies for prevention and treatment in the future.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting myeloid differentiation protein 2 ameliorates rheumatoid arthritis by inhibiting inflammation and ferroptosis via MAPK and NF-κB signaling pathways.","authors":"Lirun Zhou, Tong Yang, Shujie Zhang, Dandan Liu, Chenran Feng, Jiang Ni, Qiaoli Shi, Yanqing Liu, Yuqing Meng, Yongping Zhu, Huan Tang, Jigang Wang, Ang Ma","doi":"10.1007/s00109-025-02555-8","DOIUrl":"https://doi.org/10.1007/s00109-025-02555-8","url":null,"abstract":"<p><p>Myeloid differentiation protein 2 (MD2), a co-receptor of toll-like receptor 4 (TLR4) in the innate immune system, has emerged as a promising target for anti-inflammatory therapies. Rheumatoid arthritis (RA), a chronic autoimmune disorder characterized by persistent synovial inflammation and progressive joint destruction, remains a therapeutic challenge due to the lack of effective treatment options. In this study, we investigated the role of MD2 in the pathogenesis and progression of RA. Our findings show that MD2 is overexpressed in both the whole blood and synovial tissues of RA patients. Furthermore, MD2 expression was upregulated in collagen-induced RA mouse models. MD2 knockout significantly alleviated key symptoms of RA, including improved body weight, reduced paw swelling, and decreased bone destruction and cartilage erosion. Additionally, MD2 deficiency led to a significant reduction in serum levels of inflammatory cytokines and a decrease in the expression of inflammatory protein within synovial tissue. Notably, animal models revealed that genetic ablation of MD2 exerts potent anti-ferroptosis effects in arthritic pathophysiology. This protective effect was recapitulated at the cellular level through pharmacological interventions, where MD2-targeting inhibitors effectively attenuated lipopolysaccharide-induced ferroptotic cell death in murine macrophages, as evidenced by characteristic biomarkers including glutathione depletion and lipid peroxidation. Mechanistically, the reduction in ferroptosis and inflammation following MD2 knockout was associated with the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in the synovial tissue. These results suggest that MD2 plays a critical role in both the inflammatory response and ferroptosis, in the context of RA. Consequently, MD2 represents a key mediator of RA pathogenesis and an innovative therapeutic target for the treatment of this debilitating disease. KEY MESSAGES: MD2 expression is upregulated in synovial tissue following the onset of rheumatoid arthritis. MD2 knockout alleviates bone destruction, cartilage erosion, and inflammation in rheumatoid arthritis mice. MD2 deficiency mitigates rheumatoid arthritis in mice by inhibiting ferroptosis induced by the MAPK and NF-κB signaling pathways. MD2 may serve as a potential therapeutic target for rheumatoid arthritis.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F Ribaldi, A J Mendes, I Boscolo Galazzo, V Natale, G Mathoux, M Pievani, K O Lovblad, M Scheffler, G B Frisoni, V Garibotto, F B Pizzini
{"title":"Agreement between early-phase amyloid-PET and pulsed arterial spin labeling in a memory clinic cohort.","authors":"F Ribaldi, A J Mendes, I Boscolo Galazzo, V Natale, G Mathoux, M Pievani, K O Lovblad, M Scheffler, G B Frisoni, V Garibotto, F B Pizzini","doi":"10.1007/s00109-025-02545-w","DOIUrl":"https://doi.org/10.1007/s00109-025-02545-w","url":null,"abstract":"<p><p>Relative cerebral blood flow (rCBF), assessed using pulsed arterial spin labeling (pASL) MRI, and the standardized uptake value ratio (SUVr) in early-phase amyloid-PET (ePET) are used as proxies for brain perfusion. These methods have the potential to streamline clinical workflows and reduce the burden on patients by eliminating the need for additional procedures. While both techniques have shown good agreement with the gold standard for glucose metabolism assessment, F-fluorodeoxyglucose-PET, a direct comparison between them has yet to be fully clarified. This retrospective study aimed to compare perfusion-like data from pASL (rCBF) and ePET (SUVr) in a memory clinic cohort. We included 46 subjects (69 ± 8 years; 37 women) from the Geneva Memory Center (cognitively impaired-CI n = 29; cognitively unimpaired-CU n = 17), with available pASL and ePET. We evaluated the association between rCBF and SUVr values across 18 cortical and subcortical regions using linear regression and the within-subject coefficient of variation (wsCV). Regional differences between CU and CI groups were assessed using linear regression model corrected for age. We observed significant association between rCBF and SUVr in precuneus (β = 0.69, wsCV = 16.9), angular gyrus (β = 0.64, wsCV = 19.4), and hippocampus (β = 0.23, wsCV = 16.1). Additionally, significant differences in rCBF between CU and CI were also observed in the posterior cingulate, precuneus, calcarine, hippocampus, and composite (p < 0.05), while SUVr showed significant differences only in the hippocampus. Our findings indicate weak to moderate local correlations between the two techniques. However, both exhibited differing regional perfusion levels in CU and CI groups, with rCBF showing more regional differences between cognitive stages in comparison with SUVr. KEY MESSAGES: rCBF is assessed through pASL MRI and SUVr through ePET, both serving as proxies of brain perfusion. Weak to moderate associations between rCBF and SUVr were found in a number of brain regions. rCBF and SUVr differences between cognitive stages were observed mostly in cortical and subcortical regions respectively. Both techniques were able to identify AD perfusion-like differences expected in cognitively impaired vs unimpaired.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Valentina Pegoretti, Ate Boerema, Kim Kats, Juan M Dafauce Garcia, Roman Fischer, Roland E Kontermann, Klaus Pfizenmaier, Jon D Laman, Ulrich L M Eisel, Wia Baron
{"title":"Single intracerebroventricular TNFR2 agonist injection impacts remyelination in the cuprizone model.","authors":"Valentina Pegoretti, Ate Boerema, Kim Kats, Juan M Dafauce Garcia, Roman Fischer, Roland E Kontermann, Klaus Pfizenmaier, Jon D Laman, Ulrich L M Eisel, Wia Baron","doi":"10.1007/s00109-025-02549-6","DOIUrl":"https://doi.org/10.1007/s00109-025-02549-6","url":null,"abstract":"<p><p>The development of therapeutics that enhances the regeneration of myelin sheaths following demyelination is predicted to prevent neurodegeneration. A promising target to enhance remyelination is the immunomodulatory cytokine tumor necrosis factor alpha (TNFα) and its receptors TNFR1 and TNFR2. TNFR2 on oligodendrocyte lineage cells and microglia coordinates different protective functions, such as proliferation of oligodendrocyte progenitor cells, survival of mature oligodendrocytes, and release of anti-inflammatory cytokines, in animal models of inflammation and demyelination. Here, we find in the cuprizone model that following demyelination, fewer axons are unmyelinated in the corpus callosum at an early stage of remyelination after single TNFR2 agonist delivery in the lateral ventricle, while astrocyte and microglia number and coverage are unchanged. Towards later stages of remyelination, TNFR2 agonist treatment maintains the number of oligodendrocyte lineage cells, and large caliber axons have thinner myelin. Hence, even short-term stimulation of TNFR2 has a positive impact on the remyelination processes. This study informs further on the beneficial implications of TNFR2 signaling on oligodendrocyte lineage cells and remyelination, emphasizing its potential therapeutic value for demyelinating diseases, including multiple sclerosis. KEY MESSAGES: Single TNFR2 agonist treatment in the lateral ventricle following cuprizone-induced demyelination impacts remyelination by: Leading to a lower percentage of unmyelinated axons at early stages. Preserving the number of oligodendrocyte lineage cells in the corpus callosum at later stages. Covering large calibre axons with thinner myelin sheaths at later stages.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bruna Pereira Sorroche, Renan de Jesus Teixeira, Vinicius Gonçalves de Souza, Isabela Cristiane Tosi, Katiane Tostes, Ana Carolina Laus, Iara Viana Vidigal Santana, Vinicius de Lima Vazquez, Lidia Maria Rebolho Batista Arantes
{"title":"CD24, NFIL3, FN1, and KLRK1 signature predicts melanoma immunotherapy response and survival.","authors":"Bruna Pereira Sorroche, Renan de Jesus Teixeira, Vinicius Gonçalves de Souza, Isabela Cristiane Tosi, Katiane Tostes, Ana Carolina Laus, Iara Viana Vidigal Santana, Vinicius de Lima Vazquez, Lidia Maria Rebolho Batista Arantes","doi":"10.1007/s00109-025-02550-z","DOIUrl":"https://doi.org/10.1007/s00109-025-02550-z","url":null,"abstract":"<p><p>Melanoma poses a significant health concern due to its propensity to metastasize and its high mortality rate. Immunotherapy has emerged as a promising treatment strategy for harnessing the patient's immune system to fight tumor cells. However, not all patients respond equally to immunotherapy, highlighting the need for predictive biomarkers to identify potential responders and optimize treatment strategies. Using data from 579 immunology-related genes evaluated by the NanoString nCounter Human Immunology v2 Panel, we integrated transcriptomic data with the clinical characteristics of 35 individuals to develop a predictive signature for immunotherapy response in melanoma patients. Through comprehensive analysis, we identified 18 genes upregulated in non-responder patients and three upregulated in responder patients. In multivariate analysis, CD24, NFIL3, FN1, and KLRK1 were identified as key predictors with significant potential for forecasting treatment outcomes. We then calculated a score incorporating the expression levels of these genes. The score achieved high accuracy in discriminating responders from non-responders, with an area under the curve of 0.935 (p < 0.001). The signature was also significantly associated with progression-free survival, overall survival, and survival following immunotherapy (p < 0.001). The validation of the signature in two independent cohorts confirmed its robustness and applicability, with areas under the curve of 0.758 (p = 0.036) and 0.833 (p = 0.004), respectively. This study represents a significant advance in precision medicine for melanoma. By identifying patients unlikely to benefit from immunotherapy, our approach could help optimize treatment allocation and improve patient outcomes. KEY MESSAGES: Novel 4-gene signature predicts immunotherapy failure in melanoma. High accuracy for personalized treatment decisions. Signature associated with decreased survival for non-responders. Signature validated in independent cohorts, enhancing generalizability. Potential to tailor treatment strategies and avoid unnecessary burden to patients.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiale Tan, Yuqi Li, Jie Zhang, Beijie Qi, Jiwu Chen, Yaying Sun
{"title":"Role of aberrant activated fibro/adipogenic progenitors and suppressed ferroptosis in disused skeletal muscle atrophy and fatty infiltration.","authors":"Jiale Tan, Yuqi Li, Jie Zhang, Beijie Qi, Jiwu Chen, Yaying Sun","doi":"10.1007/s00109-025-02548-7","DOIUrl":"https://doi.org/10.1007/s00109-025-02548-7","url":null,"abstract":"<p><p>Muscle fatty infiltration (MFI) was characterized by the pathological accumulation of fat within skeletal muscle tissue. Previous studies have found that the progress of this pathological phenomenon in aging, acute muscle injury, and other conditions was triggered by the activation and adipogenic differentiation of the key cell population, fibro/adipogenic progenitors (FAPs), but there were few studies on the fat infiltration caused by disused skeletal muscle atrophy, and the regulatory role of FAPs in this situation has not been deeply explored, leaving the related molecular mechanisms still unknown. In this study, we conducted single-cell RNA sequencing on the disused skeletal muscle. The aberrant proliferation of FAPs in this state was found by subsequent analysis, along with the high expression of the ferroptosis inhibitory gene in the activated FAPs. By immunofluorescence staining, we verified the proliferation and adipogenic differentiation of FAPs, which proved the role of FAPs in fat infiltration of disused skeletal muscle. In order to further verify the relationship between ferroptosis inhibition and FAPs activation/adipogenic differentiation, we used ferrostatin-1, a commonly used ferroptosis inhibitor, to treat skeletal muscle fibroblasts and FAPs in vitro, and verified the enhancement of ferroptosis inhibition on their adipogenic/fibrogenic ability. Our study pinpointed the effect of aberrant activation of FAPs on MFI in disused skeletal muscle, and preliminarily recognized the potential effect of ferroptosis on the adipogenic differentiation of FAPs. KEY MESSAGES: • Muscle fatty infiltration (MFI) was characterized by the pathological accumulation of fat within skeletal muscle. Fibro/adipogenic progenitors (FAPs) were thought to be crucial regulators of MFI, but their correlations in disused skeletal muscle were unspecified. • In this study, we conducted single-cell RNA sequencing on the disused skeletal muscle and recognized the aberrant proliferation of FAPs along with the upregulated ferroptosis inhibition genes in this status. • Subsequently, we used ferrostatin-1 (ferroptosis inhibitor) to treat skeletal muscle fibroblasts in vitro, and verified the enhancement of ferroptosis inhibition on their adipogenic/fibrogenic ability. • Our study pinpointed the effect of aberrant activation of FAPs on MFI in disused skeletal muscle, and preliminarily recognized the potential effect of ferroptosis on the adipogenic differentiation of FAPs.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Regie Lyn P Santos-Cortez, Christina L Elling, Helen Z Gomez, Elisabet Einarsdottir, Juha Kere, Petri S Mattila, Lena Hafrén, Allen F Ryan
{"title":"Rare and low-frequency variants in families with otitis media.","authors":"Regie Lyn P Santos-Cortez, Christina L Elling, Helen Z Gomez, Elisabet Einarsdottir, Juha Kere, Petri S Mattila, Lena Hafrén, Allen F Ryan","doi":"10.1007/s00109-025-02537-w","DOIUrl":"10.1007/s00109-025-02537-w","url":null,"abstract":"<p><p>Otitis media is a highly frequent diagnosis in children that causes significant morbidity but remains understudied as a genetic trait despite significant heritability in families. To identify rare or low-frequency variants within genes that confer susceptibility to otitis media, exome sequence data of 287 individuals from 243 families were analyzed. Identified variants were tested for co-segregation with otitis media in family members. Genome sequence data from a case-control cohort was imputed and analyzed for association of specific genes with otitis media. Single-cell RNA-sequence data of identified genes were noted in acutely infected mouse middle ears. Thirty-three variants within 24 genes co-segregated with otitis media in 28 families, of which 18 variants were considered pathogenic or likely pathogenic. An additional 81 variants in 21 of the same genes were identified in 83 unrelated probands with otitis media. Of the 24 genes, 12 were associated with otitis media in mouse models, while 15 genes were replicated from previous human studies. A common variant EYA4 c.829G > A was associated with OM in the case-control cohort. Using network analysis, 22 of the 24 genes were connected in a subnetwork enriched in various signaling pathways, Th1/Th2/Th17 cell differentiation, and viral infections. Majority (87.5%) of the identified genes were expressed in mouse middle ear cells, with differential expression after acute infection. The identification of novel genes and variants for susceptibility to otitis media will be useful in future risk screening and clinical management in children that require a more personalized approach due to poor response to standard treatments. KEY MESSAGES: Thirty-three variants in 24 genes were identified in 28 families with otitis media. Eighteen of these variants within 10 genes were considered (likely) pathogenic. A common variant EYA4 c.829G > A was associated with OM in a case-control cohort. The novel genes were differentially expressed in mouse middle ear post-infection. Genetic screening could identify children for targeted treatment for otitis media.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"559-570"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Litao Chen, Lechen Hu, Han Chang, Jianing Mao, Meng Ye, Xiaofeng Jin
{"title":"DNA-RNA hybrids in inflammation: sources, immune response, and therapeutic implications.","authors":"Litao Chen, Lechen Hu, Han Chang, Jianing Mao, Meng Ye, Xiaofeng Jin","doi":"10.1007/s00109-025-02533-0","DOIUrl":"10.1007/s00109-025-02533-0","url":null,"abstract":"<p><p>Cytoplasmic DNA-RNA hybrids are emerging as important immunogenic nucleic acids, that were previously underappreciated. DNA-RNA hybrids, formed during cellular processes like transcription and replication, or by exogenous pathogens, are recognized by pattern recognition receptors (PRRs), including cGAS, DDX41, and TLR9, which trigger immune responses. Post-translational modifications (PTMs) including ubiquitination, phosphorylation, acetylation, and palmitoylation regulate the activity of PRRs and downstream signaling molecules, fine-tuning the immune response. Targeting enzymes involved in DNA-RNA hybrid metabolism and PTMs regulation offers therapeutic potential for inflammatory diseases. Herein, we discuss the sources, immune response, and therapeutic implications of DNA-RNA hybrids in inflammation, highlighting the significance of DNA-RNA hybrids as potential targets for the treatment of inflammation.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"511-529"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ONC201 exerts oncogenic effects beyond its mitochondria-disturbing role in neuroblastoma subsets.","authors":"Jyun-Hong Jiang, Yu-Han Lin, Pei-Lin Liao, Ting-Ya Chen, Hui-Ching Chuang, Chao-Cheng Huang, Wen-Ming Hsu, Jiin-Haur Chuang, Wei-Shiung Lian","doi":"10.1007/s00109-025-02541-0","DOIUrl":"10.1007/s00109-025-02541-0","url":null,"abstract":"<p><p>Neuroblastoma (NB) is a formidable challenge in pediatric oncology due to its intricate molecular landscape, necessitating multifaceted therapeutic approaches. ONC201 is an imipridone antibiotic compound with a promising drug candidate leveraging its potent anticancer properties against the mitochondrial proteases ClpP and ClpX. Despite demonstrating early clinical promise, particularly in MYCN-amplified NB, its efficacy in non-MYCN-amplified NB remains a subject worthy of investigation. In this study, we extended the coverage of ONC201 to treat non-MYCN-amplified NB, and our data implicated ONC201's inability to reduce tumor growth in animal models harboring SK-N-AS or SK-N-FI cell lines. Interestingly, ONC201 induced the expression of oncogenic markers c-Myc and LGR5 while downregulating the tumor suppressor ATRX. While it fails to attenuate tumor neovascularization in non-MYCN-amplified NB xenografts, its effectiveness differs from that of its MYCN-amplified counterpart. Rho zero (ρ0)-SK-N-AS cells treated with ONC201 showed comparable observed trends in parental SK-N-AS cells, including LGR5 upregulation and ATRX downregulation, suggesting that ONC201's multifaceted actions extend beyond mitochondrial targets. Our elucidation highlights the need to discern molecular signatures when deploying ONC201 monotherapy against NB, which lacks MYCN-amplification.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":"103 5","pages":"571-582"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}