Molecular Medicine最新文献

{"title":"Cytoplasmic HMGB1 promotes the activation of JAK2-STAT3 signaling and PD-L1 expression in breast cancer.","authors":"Ju-Young Han, Woo Joong Rhee, Jeon-Soo Shin","doi":"10.1186/s10020-025-01235-0","DOIUrl":"10.1186/s10020-025-01235-0","url":null,"abstract":"<p><strong>Background: </strong>High-mobility group box 1 (HMGB1) plays various roles depending on its subcellular localization. Extracellular HMGB1 interacts with receptors, such as toll-like receptor 4 and receptor for advanced glycation end products (RAGE), promoting cell proliferation, survival, and migration in cancer cells. It also increases the expression of programmed death-ligand 1 (PD-L1) in cancer cells by binding to RAGE. However, the effect of intracellular HMGB1 on the regulation of immune checkpoints such as PD-L1 has not been well characterized. In this study, we aimed to investigate the effects of intracellular HMGB1 on PD-L1 expression in breast cancer cells.</p><p><strong>Methods: </strong>Human and mouse triple-negative breast cancer cells, MDA-MB-231 and 4T1, along with HMGB1-deficient mouse embryonic fibroblast cells, were cultured. HMGB1 overexpression was achieved using a Myc-tagged plasmid, while siHMGB1 constructs were used for gene silencing. Quantitative reverse-transcriptase PCR and western blot analysis were performed to assess gene and protein expressions. Confocal imaging, immunoprecipitation, and proximity ligation assays were used to investigate HMGB1 localization and Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) interactions. In vivo experiments were performed using tumor-bearing mice treated with STAT3 and HMGB1 inhibitors. Statistical analyses were performed using Student's t-tests, one-way analysis of variance, Pearson's correlation, and Kaplan-Meier survival analysis, with significance set at p < 0.05.</p><p><strong>Results: </strong>In breast cancer cells, HMGB1 translocation from the nucleus to the cytoplasm increased the JAK2-STAT3 interaction and induced STAT3 phosphorylation, leading to increased STAT3 target signaling, including the epithelial-mesenchymal transition (EMT) phenotype and PD-L1 expression. Inhibition of nucleo-cytoplasmic translocation of HMGB1 decreased STAT3 phosphorylation and PD-L1 expression. Furthermore, HMGB1 enhanced breast cancer cell migration, invasion, and EMT, contributing to tumor growth in an in vivo mouse model that were mitigated by the HMGB1-targeted approach.</p><p><strong>Conclusions: </strong>These findings underscore the critical role of intracellular HMGB1 in modulating PD-L1 expression via the JAK2-STAT3 signaling pathways in breast cancer and suggest that targeting HMGB1 translocation is a promising strategy for breast cancer treatment.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"197"},"PeriodicalIF":6.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102122","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":"Clinically relevant pseudoexons of the GALNS gene and their antisense-based correction.","authors":"Igor Bychkov, Elza Shchukina, Ekaterina Zakharova","doi":"10.1186/s10020-025-01243-0","DOIUrl":"10.1186/s10020-025-01243-0","url":null,"abstract":"<p><strong>Background: </strong>Biallelic pathogenic variants in the GALNS gene lead to Mucopolysaccharidosis Type IVA (MPS IVA), a rare lysosomal storage disorder. GALNS encodes the enzyme N-acetylgalactosamine-6-sulfatase, whose deficiency causes accumulation of glycosaminoglycans and leads to a broad spectrum of clinical manifestations primarily affecting the osteoarticular system. Several studies have shown that, in 10%-15% of patients with the biochemical phenotype of MPS IVA, standard molecular genetic testing fails to identify one or both causative variants in the GALNS gene.</p><p><strong>Methods: </strong>We performed an in-depth investigation of GALNS' splicing, with a special focus on deep-intronic mutations that lead to activation of pseudoexons (PEs). Using bioinformatic tools, we analyzed all deep-intronic variants in GALNS available in public databases and subjected the most relevant ones to in vitro analyses using minigenes.</p><p><strong>Results: </strong>We characterized eight PE-activating variants, one of which (c.121-210C > T) represents a recurrent pathogenic variant which has long been hidden behind the mask of a polymorphic variant. In addition, we demonstrate that GALNS' splicing can produce a diverse range of mRNA isoforms containing so-called wild-type PEs, which are present at low levels as part of non-productive splicing, and weak canonical exons which are prone to skipping. We show that PE-activating variants cluster within wild-type PEs, highlighting the need for closer scrutiny of these regions during genetic testing. Finally, we applied modified U7 small nuclear RNAs and circular RNAs to efficiently block the identified PEs and pave the way for personalized antisense-based therapy for MPS IVA patients.</p><p><strong>Conclusion: </strong>The results of this study expand the understanding of GALNS gene splicing, indicating hotspots for splicing mutations. The presented data not only help to increase the diagnostic yield for MPS IVA but also unveil new therapeutic approaches for a number of MPS IVA patients.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"196"},"PeriodicalIF":6.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094270","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":"Unveiling metabolic pathways in the hyperglycemic bone: bioenergetic and proteomic analysis of the bone tissue exposed to acute and chronic high glucose.","authors":"Rita Araújo, Raquel L Bernardino, Mariana P Monteiro, Pedro S Gomes","doi":"10.1186/s10020-025-01251-0","DOIUrl":"10.1186/s10020-025-01251-0","url":null,"abstract":"<p><strong>Background: </strong>Bone fragility due to poor glycemic control is a recognized complication of diabetes, but the mechanisms underlying diabetic bone disease remain poorly understood. Despite the importance of bioenergetics in tissue functionality, the impact of hyperglycemia on bone bioenergetics has not been previously investigated.</p><p><strong>Objective: </strong>To determine the effects of high glucose exposure on energy metabolism and structural integrity in bone tissue using an ex vivo organotypic culture model of embryonic chick femur.</p><p><strong>Methods: </strong>Femora from eleven-day-old Gallus gallus embryos were cultured for eleven days under physiological glucose conditions (5.5 mM, NG), chronic high glucose exposure (25 mM, HG-C), or acute high glucose exposure (25 mM, HG-A). Bioenergetic assessments (Seahorse assays), proteomic analysis (liquid chromatography-mass spectrometry), histomorphometric and microtomographic evaluations, and oxidative stress measurements (carbonyl content assay) were performed. Statistical analyses were conducted using IBM® SPSS® Statistics (v26.0). The Mann-Whitney nonparametric test was used for group comparisons in microtomographic analysis, ALP activity, and carbonyl content assays. For Seahorse assay results, ANOVA with Tukey's post-hoc test was applied after confirming data homoscedasticity with Levene's test.</p><p><strong>Results: </strong>Chronic high glucose exposure reduced bone mineral deposition, altered histomorphometric indices, and suppressed key osteochondral development regulators. Acute high glucose exposure enhanced glycolysis and oxidative phosphorylation, while chronic exposure caused oxygen consumption uncoupling, increased ROS generation, and downregulated mitochondrial proteins critical for bioenergetics. Elevated oxidative stress was confirmed in the chronic high glucose group.</p><p><strong>Conclusion: </strong>Chronic high glucose exposure disrupted bone bioenergetics, induced mitochondrial dysfunction, and compromised bone structural integrity, emphasizing the metabolic impact of hyperglycemia in diabetic bone disease.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"194"},"PeriodicalIF":6.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094432","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":"m6A-lncRNA landscape highlights reduced levels of m6A modification in glioblastoma as compared to low-grade glioma.","authors":"Giedrius Steponaitis, Rugile Dragunaite, Rytis Stakaitis, Amit Sharma, Arimantas Tamasauskas, Daina Skiriute","doi":"10.1186/s10020-025-01254-x","DOIUrl":"10.1186/s10020-025-01254-x","url":null,"abstract":"<p><strong>Background: </strong>Efforts to understand the interplay between m6A (N6-methyladenosine) modification and long non-coding RNAs (lncRNAs) in the pathogenesis of various diseases, including cancer, have recently attracted considerable attention.</p><p><strong>Methods: </strong>Herein, we profiled epitranscriptome-wide m6A modifications within lncRNAs at single m6A site resolution across different grades of gliomas (Glioblastomas (GB): n = 17, Low grade gliomas (LGG): n = 9) using direct RNA long-read sequencing.</p><p><strong>Results: </strong>Our analysis demonstrated that, 1) 98.5% of m6A-modified RRACH motifs were present within mRNA transcripts, while only 1.16% were conspicuous within lncRNAs. Importantly, LGGs exhibited a higher m6A abundance (23.73%) compared to the GB transcriptome (15.84%). 2) The m6A profiles of lncRNAs differed significantly between gliomas, with unsupervised cluster analysis revealing two clusters (C1, C2). LGG dispersed between C1 and C2 clusters while GB stayed mainly in C1. Clinical feature association analysis between m6A clusters showed the tendency of m6A to be associated with higher malignancy grade (p = 0.053), while significant association was observed with higher Ki-67 proliferation index (p = 0.04), and tumor location (p < 0.01). Specifically, brain tumors located in cerebellum (n = 3) were highly m6A modified on lncRNAs as compared to tumors in other locations (frontal lobe, n = 5, p = 0.003; frontotemporal lobe, n = 2, p = 0.08; occipital, n = 2, p = 0.038; parietal, n = 2, p = 0.007; temporal, n = 11, p < 0.001). Cox regression analysis showed that the status of lncRNAs m6A modifications had no significant value in predicting post-surgical survival time in our GB or LGG cohorts. The trend of higher lncRNA expression in m6A methylated group was observed for the majority of lncRNAs, while only MIR9-1HG (r = 0.439, p = 0.028) and ZFAS1 (r = 0.609, p < 0.05) m6A showed statistically significant positive correlations in gliomas. A high-resolution m6A study revealed that mRNA levels of m6A writers and erasers in gliomas do not reflect global m6A methylation.</p><p><strong>Conclusions: </strong>Overall, we provide evidence that m6A lncRNAs are strongly modulated in gliomas, representing biologically distinct subgroups. Ten novel differentially methylated lncRNAs were identified in gliomas, which might exert regulatory role in glioma cells. These findings may provide a basis for further deeper research on the role of m6A lncRNAs in gliomas.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"195"},"PeriodicalIF":6.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094342","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":"Endogenous Galectin-8 protects against Th17 infiltration and fibrosis following acute kidney injury.","authors":"Elisa Perez-Moreno, Adely de la Peña, Tomás Toledo, Javiera Saez, Francisca Pérez-Molina, Sofía Espinoza, Claudia Metz, Nicole Díaz-Valdivia, Lorena Azócar, Carolina Prado, Rodrigo Pacheco, Fabian Segovia-Miranda, Alejandro S Godoy, Cristian A Amador, Teo Feuerhake, Alfonso González, Andrea Soza","doi":"10.1186/s10020-025-01245-y","DOIUrl":"10.1186/s10020-025-01245-y","url":null,"abstract":"<p><strong>Background: </strong>Acute kidney injury (AKI) is a serious clinical condition characterized by a rapid decline in renal function, often progressing to chronic kidney disease (CKD) and fibrosis. The endogenous mechanisms influencing kidney injury resolution or maladaptive repair remain poorly understood. Galectin-8 (Gal-8), a tandem-repeat β-galactoside-binding lectin, plays a role in epithelial cell proliferation, epithelial-mesenchymal transition, and immune regulation, all of which are critical in AKI outcomes. While exogenous Gal-8 administration has shown renoprotective effects, its endogenous role in kidney injury progression and resolution remains unclear.</p><p><strong>Methods: </strong>To investigate the endogenous role of Gal-8 in AKI, we compared the responses of Gal-8 knockout (Gal-8-KO; Lgals8^-/- bearing a β-gal cassette under the Lgals8 gene promoter) and wild-type (Lgals8^+/+) mice in a nephrotoxic folic acid (FA)-induced AKI model. Renal Gal-8 expression was assessed by β-galactosidase staining, lectin-marker colocalization, and RT-qPCR. Renal function, structure, and immune responses were evaluated at the acute (day 2) and fibrotic (day 14) phases of injury. Plasma creatinine levels were measured to assess renal function, while histological analyses evaluated tubular damage, renal inflammation, and extracellular matrix deposition. Flow cytometry was performed to characterize the immune response, focusing on pro-inflammatory T cells.</p><p><strong>Results: </strong>Galectin-8 was predominantly expressed in the renal cortex, localizing to tubules, glomeruli, and blood vessels, with its levels decreasing by half following AKI. Both Lgals8^+/+ and Lgals8^-/- mice exhibited similar renal function and structure impairments during the acute phase, though Lgals8^+/+ mice showed slightly worse damage. By the fibrotic phase, Lgals8^-/- mice exhibited more pronounced cortical damage and fibrosis, characterized by increased type I and III collagen deposition and enhanced Th17 cell infiltration, while myofibroblast activation remained comparable to that of Lgals8^+/+ mice.</p><p><strong>Conclusions: </strong>Endogenous Gal-8 does not significantly protect the kidney during the acute phase and is dispensable for cell proliferation and death in response to AKI. However, it is crucial in preventing maladaptive repair by regulating extracellular matrix homeostasis and mitigating fibrosis. Additionally, Gal-8 contributes to inflammation resolution by limiting persistent immune cell infiltration, particularly IL-17-secreting cells.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"192"},"PeriodicalIF":6.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078740","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":"Science tikkun: a bioscience pandemic framework in a Hebrew tradition of global repair.","authors":"Peter Hotez","doi":"10.1186/s10020-025-01244-z","DOIUrl":"10.1186/s10020-025-01244-z","url":null,"abstract":"<p><p>Over the past decade we have seen a steady increase in dangerous pandemic threats. They include two major Ebola epidemics and cholera in Africa; dengue, Zika, yellow fever in the Americas; a COVID-19 pandemic; and H5N1 in Texas. This is happening because of a confluence of modern forces including urbanization, deforestation, and climate change. Yet as pandemics emerge on a crowded and warming planet, anti-science disinformation and antisemitism impede our response. Science tikkun is an overarching framework for repair and redress. It honors the legacy of Maimonides, Teilhard de Chardin, and others who have sought reconciliation between science and religion.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"193"},"PeriodicalIF":6.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086401","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 diacylglycerol O-acyltransferase 1 provides neuroprotection by inhibiting ferroptosis in ischemic stroke.","authors":"Youjie Zeng, Ren Guo, Songhua Chen, Yuxin Lin, Si Cao, Xia Wang, Siyi Zhang, Huilin Xu, Wenxiang Qing, Heng Yang, Wen Ouyang","doi":"10.1186/s10020-025-01255-w","DOIUrl":"10.1186/s10020-025-01255-w","url":null,"abstract":"<p><strong>Background: </strong>Diacylglycerol O-acyltransferase 1 (DGAT1) is crucial for triglyceride synthesis, yet its role in ischemic stroke remains unclear. This study investigated DGAT1 in ischemic stroke using middle cerebral artery occlusion (MCAO) rat models and highly differentiated PC12 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R).</p><p><strong>Methods: </strong>The therapeutic effects of DGAT1 inhibition in MCAO rats were assessed using the Zea-Longa score and 2,3,5-Triphenyltetrazolium chloride (TTC) staining. The effects on highly differentiated PC12 cells subjected to OGD/R were evaluated using the Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays. Ferroptosis-related mitochondrial damage was evaluated using transmission electron microscope. Additionally, the mechanisms by which DGAT1 inhibition regulates ferroptosis were further explored via immunohistochemistry, immunofluorescence, Western blotting, qPCR, JC-1 assay, and reactive oxygen species (ROS) detection.</p><p><strong>Results: </strong>DGAT1 expression was elevated in both MCAO and OGD/R models. The DGAT1 inhibitor A 922500 improved neurological deficits, reduced infarct volume, and minimized neuronal loss in MCAO rats, while also enhancing cell viability and reducing LDH levels in OGD/R-treated PC12 cells. DGAT1 inhibition significantly alleviated ferroptosis in MCAO rats, as indicated by (i) reduced mitochondrial shortening and cristae disruption, (ii) decreased 4-HNE levels, (iii) reduced MDA and increased SOD, and (iv) lowered levels of inflammatory factors (IL-6, MCP-1, and TNF-α). Moreover, both in vivo and in vitro experiments showed that DGAT1 inhibition significantly increased Gpx4 levels, whereas lentiviral delivery of Gpx4 shRNA markedly reversed its beneficial effects. In MCAO rats, Gpx4 shRNA significantly elevated 4-HNE levels and exacerbated ferroptosis-related mitochondrial damage. In vitro, DGAT1 inhibition increased mitochondrial membrane potential and reduced ROS, whereas rotenone, a mitochondrial function inhibitor, decreased Gpx4 and impaired cell viability. Furthermore, DGAT1 inhibition significantly upregulated the key β-oxidation gene Cpt1a, whereas etomoxir, a β-oxidation inhibitor, reduced cell viability and mitochondrial membrane potential, increased ROS, and downregulated Gpx4.</p><p><strong>Conclusions: </strong>Our study suggests that DGAT1 inhibition may enhance β-oxidation and mitochondrial function, thereby increasing Gpx4 levels, suppressing ferroptosis, and ultimately exerting neuroprotective effects in ischemic stroke.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"191"},"PeriodicalIF":6.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078811","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":"Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration.","authors":"Wenyi Tang, Ruyi Zhai, Jun Ma, Gezhi Xu","doi":"10.1186/s10020-025-01250-1","DOIUrl":"10.1186/s10020-025-01250-1","url":null,"abstract":"<p><strong>Background: </strong>Retinal degeneration is a leading cause of blindness worldwide. The induction of ferroptosis has been identified as an important mechanism contributing to the loss of photoreceptors in retinal degeneration. Lipocalin-2 (LCN2) exhibits iron-regulatory properties and may modulate cell viability in various diseases. However, the effects of LCN2 on ferroptosis in retinal degeneration remain unclear.</p><p><strong>Methods: </strong>A light-induced injury model using 661W photoreceptor cells and a light-induced retinal degeneration male rat model were established. LCN2 protein expression was assessed by western blotting. The effects of LCN2 on ferroptosis in vitro were investigated by using recombinant LCN2 protein (rLCN2) and small-interfering RNA (siRNA) targeting LCN2 (siLCN2). Fe²⁺, malondialdehyde (MDA), tripeptide glutathione (GSH) levels, and the expression of ferroptosis-associated proteins (solute carrier family 7 member 11 [SLC7A11] and glutathione peroxidase-4 [GPX4]) were measured. A phosphokinase array and western blotting were performed to elucidate the mechanisms underlying LCN2-modulated photoreceptor ferroptosis. Additionally, the protective effects of LCN2 knockdown using adeno-associated virus (AAV)-expressing short hairpin RNA (shRNA) targeting LCN2 (AAV-shRNA-LCN2) on retinal structure and function in vivo were evaluated by hematoxylin and eosin staining and electroretinography.</p><p><strong>Results: </strong>LCN2 expression was significantly upregulated following light exposure. Treatment with rLCN2 significantly induced ferroptosis in photoreceptor cells, as shown by decreased cell viability, increased Fe²⁺ levels, inhibition of SLC7A11 and GPX4 expression, depletion of GSH, and enhanced MDA levels, whereas siLCN2 protected against these effects. Exposure of photoreceptor cells to rLCN2 activated c-Jun N-terminal kinase (JNK), and administration of the JNK inhibitor SP600125 protected photoreceptor cells from ferroptosis. Lastly, AAV-shRNA-LCN2 administration inhibited light-induced ferroptosis in the retina, and protected the retinal structure and function in vivo.</p><p><strong>Conclusion: </strong>LCN2 is a key regulator of light-induced ferroptosis in photoreceptors by modulating the JNK pathway. Therefore, LCN2 presents a new target for the treatment of retinal degeneration.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"190"},"PeriodicalIF":6.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078899","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":"AEOL-induced NRF2 activation and DWORF overexpression mitigate myocardial I/R injury.","authors":"Maria Del Carmen Asensio-Lopez, Miriam Ruiz-Ballester, Silvia Pascual-Oliver, Francisco Jose Bastida-Nicolas, Yassine Sassi, Jose Javier Fuster, Domingo Pascual-Figal, Fernando Soler, Antonio Lax","doi":"10.1186/s10020-025-01242-1","DOIUrl":"10.1186/s10020-025-01242-1","url":null,"abstract":"<p><strong>Background: </strong>The causal relationship between the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the preservation of SERCA2a function in mitigating myocardial ischemia-reperfusion (mI/R) injury, along with the associated regulatory mechanisms, remains incompletely understood. This study aims to unravel how NRF2 directly or indirectly influences SERCA2a function and its regulators, phospholamban (PLN) and Dwarf Open Reading Frame (DWORF), by testing the pharmacological repositioning of AEOL-10150 (AEOL) in the context of mI/R injury.</p><p><strong>Methods: </strong>C57BL6/J, Nrf2 knockout (Nrf2^-/-), and wild-type (Nrf2^+/+) mice, as well as human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) were subjected to I/R injury. Gain/loss of function techniques, RT-qPCR, western blotting, LC/MS/MS, and fluorescence spectroscopy were utilized. Cardiac dimensions and function were assessed by echocardiography.</p><p><strong>Results: </strong>In the early stages of mI/R injury, AEOL administration reduced mitochondrial ROS production, decreased myocardial infarct size, and improved cardiac function. These effects were due to NRF2 activation, leading to the overexpression of the micro-peptide DWORF, consequently enhancing SERCA2a activity. The cardioprotective effect induced by AEOL was diminished in Nrf2^-/- mice and in Nrf2/Dworf knockdown models in hiPSCMs subjected to simulated I/R injury. Our data show that AEOL-induced NRF2-mediated upregulation of DWORF disrupts the phospholamban-SERCA2a interaction, leading to enhanced SERCA2a activation and improved cardiac function.</p><p><strong>Conclusions: </strong>Taken together, our study reveals that AEOL-induced NRF2-mediated overexpression of DWORF enhances myocardial function through the activation of the SERCA2a offering promising therapeutic avenues for mI/R injury.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"189"},"PeriodicalIF":6.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078684","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":"Comprehensive single-cell transcriptomic reveals different destinies of melanocytes and dynamic changes of immune microenvironment in a psychological stress-induced leukoderma and leukotrichia mouse model.","authors":"Xuechen Cao, Yongkai Yu, Hang Yao, Yujie Zheng, Jiawei Lu, Yifei Feng, Tongxin Pei, Ziyu Li, Ming Lu, Yan Lu","doi":"10.1186/s10020-025-01236-z","DOIUrl":"10.1186/s10020-025-01236-z","url":null,"abstract":"<p><strong>Background: </strong>Vitiligo is an acquired skin depigmentation disorder often accompanied by leukoderma and leukotrichia. Half of vitiligo patients experience episodes of stress.</p><p><strong>Methods: </strong>We established a chronic unpredictable mild stimulation (CUMS) model in C57BL/6 J mice to simulate chronic mental stress-induced leukoderma and leukotrichia. Single-cell RNA sequencing was performed to determine the immune landscape and to characterize the relationship between immune-stromal cells. Immunohistochemistry was employed for validation.</p><p><strong>Results: </strong>We discovered a similar pro-inflammatory micro-environment composed of keratinocytes and fibroblasts similar to that in human vitiligo. Macrophages in CUMS mice expressed high levels of inflammatory factors and were inclined to an M1 pro-inflammatory phenotype. Two distinct clusters of melanocytes were also identified: Mel2, defined as melanocyte stem cells, and Mel3, defined as mature melanocytes. Mel2 cells were prone to pyroptosis and necroptosis, while Mel3 cells were susceptible to oxidative stress, mitochondrial dysfunction, and ferroptosis. Compared with control mice, higher expression of CXCL16 on dendritic cells and of the CXCL16 ligand, CXCR6, on γδT cells were observed in leukoderma. Dendritic cells and natural killer T cells in the CUMS mouse spleen exhibited elevated levels of CXCL16 and CXCR6, respectively. Activation of the CXCL16-CXCR6 axis and a non-specific immune response in our CUMS model might imitate chronic mental stress-induced vitiligo in humans better than CD8 + cytotoxic T lymphocyte-mediated models.</p><p><strong>Conclusions: </strong>We discovered two melanocyte clusters with distinct fates and a pro-inflammatory micro-environment with CXCL16-CXCR6 axis activation of antigen-presenting cells and other innate immunocytes that might provide new insights into the pathogenesis of stress-induced vitiligo.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"186"},"PeriodicalIF":6.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018308","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}