Journal of Molecular Medicine-Jmm最新文献

{"title":"Hepatic microtubule destabilization facilitates liver fibrosis in the mouse model of Wilson disease.","authors":"Som Dev, Yixuan Dong, James P Hamilton","doi":"10.1007/s00109-025-02535-y","DOIUrl":"10.1007/s00109-025-02535-y","url":null,"abstract":"<p><p>Wilson disease (WD) is a potentially fatal metabolic disorder caused by the inactivation of the copper (Cu) transporter ATP7B, resulting in systemic Cu overload and fibroinflammatory liver disease. The molecular mechanism and effects of elevated Cu on cytoskeletal dynamics in liver fibrogenesis are not clear. Here, we tested the regulation of hepatic cytoskeleton and fibrogenesis with respect to Cu overload in WD. Atp7b^-/- (knockout) mice with established liver disease, hepatocyte-specific Atp7b△^Hep knockout mice without fibroinflammatory disease, and the age-and sex-matched controls were compared using Western blotting, real-time quantitative reverse transcription PCR (qRT-PCR), immunohistochemical (IHC) staining and transcriptomics (RNA-sequencing) analysis. In Atp7b^-/- mice with developed liver disease, there is a significant increase in cytoskeletal protein expression with a reduction in α-tubulin acetylation. In these mice before the onset of liver pathology, no significant changes in cytoskeletal nor hepatic stellate cell activation are observed. As hepatic copper levels rise, an increase in cytoskeletal proteins with a decrease in acetylated-α-tubulin/α-tubulin ratio occurs. RNA-sequencing, qRT-PCR, and immunostaining confirm that the tubulin is upregulated at the transcriptional level and hepatocytes are the primary source of early tubulin increases before fibrosis. An increase in α-tubulin with a decrease in α-tubulin acetylation via Hdac6 and Sirt2 induction facilitates fibrosis as reflected by concomitant increases in desmin and α-SMA immunostaining in Atp7b^-/- mice at 20 weeks. Moreover, strongly positive correlations between α-tubulin and α-tubulin deacetylase with the expression of liver fibrosis markers are observed in animal and human WD. Hepatocyte-specific Atp7b△^Hep mice lack significant changes in tubulin as well as fibrosis despite hepatic steatosis. This study provides evidence that microtubule destabilization causes cytoskeletal rearrangement and facilitates hepatic stellate cell (HSC) activation and fibrosis in the murine model of WD. KEY MESSAGES: Hepatic cytoskeleton system is induced in Wilson disease. Hepatic microtubules acetylation is dysregulated in murine Wilson disease. Microtubules destabilization is positively associated with liver fibrosis in Wilson disease. Microtubules destabilization concomitant with fibrogenesis exacerbates WD progression.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"531-545"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722359","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}

{"title":"Sphingosine kills Mycobacteria and suppresses mycobacterial lung infections.","authors":"Yuqing Wu, Fabian Schnitker, Yongjie Liu, Simone Keitsch, Federico Caicci, Fabian Schumacher, Andrea Riehle, Barbara Pollmeier, Jan Kehrmann, Burkhard Kleuser, Markus Kamler, Ildiko Szabo, Heike Grassmé, Erich Gulbins","doi":"10.1007/s00109-025-02534-z","DOIUrl":"10.1007/s00109-025-02534-z","url":null,"abstract":"<p><p>Tuberculous mycobacterial infections pose a substantial global health burden because of their prevalence and multi-drug resistance. The current approach to tackling these infections primarily involves developing new antibiotics or combining existing ones, an approach that often proves ineffective in the specific targeting of mycobacteria. We investigated the effect of sphingosine on tuberculous Mycobacteria in vitro and mycobacterial infections in vivo to test whether sphingosine could potentially be used as a novel drug against tuberculosis. Sphingosine inhibited mycobacterial growth and eradicated mycobacteria in vitro. Mechanistically, sphingosine increased bacterial membrane permeability and induced marked changes on the bacterial plasma membrane evidenced by electron microscopy studies. Administration of sphingosine in a mouse model of pulmonary infection with Bacillus Calmette-Guérin (BCG) greatly reduced the number of bacteria in the lung and prevented pulmonary inflammation. Furthermore, infection of ex vivo human lung tissue samples with BCG and treatment with sphingosine showed that sphingosine also kills BCG in human bronchi. Our findings suggest that sphingosine may be a potential therapeutic intervention against mycobacterial infections. KEY MESSAGES: Sphingosine inhibits mycobacterial growth in vitro. Sphingosine disrupts bacterial membrane integrity. Sphingosine reduces bacterial load in mouse pulmonary infection model. Sphingosine eradicates mycobacteria in human bronchi ex vivo.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"547-558"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736245","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}

{"title":"Cardiovascular dysfunction and altered lysosomal signaling in a murine model of acid sphingomyelinase deficiency.","authors":"Yun-Ting Wang, Alexandra K Moura, Rui Zuo, Kiana Roudbari, Jenny Z Hu, Saher A Khan, Zhengchao Wang, Yangping Shentu, Mi Wang, Pin-Lan Li, Jiukuan Hao, Yang Zhang, Xiang Li","doi":"10.1007/s00109-025-02542-z","DOIUrl":"https://doi.org/10.1007/s00109-025-02542-z","url":null,"abstract":"<p><p>Niemann-Pick Disease (NPD) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by the deficiency of acid sphingomyelinase (ASMD), which is encoded by the Smpd1 gene. ASMD impacts multiple organ systems in the body, including the cardiovascular system. This study is the first to characterize cardiac pathological changes in ASMD mice under baseline conditions, offering novel insights into the cardiac implications of NPD. Using histological analysis, biochemical assays, and echocardiography, we assessed cardiac pathological changes and function in Smpd1^-/- mice compared to Smpd1^+/+ littermate controls. Immunofluorescence and biochemical assays demonstrated that ASMD induced lysosomal dysfunction, as evidenced by the accumulation of lysosomal-associated membrane proteins, lysosomal protease, and autophagosomes in pericytes and cardiomyocytes. This lysosomal dysfunction was accompanied by pericytes and cardiomyocytes inflammation, characterized by increased expression of caspase1 and inflammatory cytokines, and infiltration of inflammatory cells in the cardiac tissues of Smpd1^-/- mice. In addition, histological analysis revealed increased lipid deposition and cardiac steatosis, along with pericyte-to-myofibroblast transition (PMT) and interstitial fibrosis in Smpd1^-/- mice. Moreover, echocardiography further demonstrated that Smpd1^-/- mice developed coronary microvascular dysfunction (CMD), as evidenced by decreased coronary blood flow velocity and increased coronary arteriolar wall thickness. Additionally, these mice exhibited significant impairments in systolic and diastolic cardiac function, as shown by a reduced ejection fraction and prolonged left ventricular relaxation time constant (Tau value). These findings suggest that ASMD induces profound pathological changes and vascular dysfunction in the myocardium, potentially driven by mechanisms involving lysosomal dysfunction as well as both pericytes and cardiac inflammation. KEY MESSAGES: Lysosomal dysfunction in ASMD leads to impaired autophagic flux in cardiac pericytes ASMD causes cardiac inflammation with leukocyte and M2 macrophage infiltration Lipid buildup in the pericytes, fibroblasts and myocardium lead to cardiac steatosis Enhanced cardiac fibrosis in ASMD links to pericyte-to-myofibroblast transition ASMD results in coronary microvascular and diastolic and systolic cardiac dysfunction.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":"103 5","pages":"599-617"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003647","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":"Increased ZNF83 is a potential prognostic biomarker and regulates oxidative stress-induced ferroptosis in clear cell renal cell carcinoma.","authors":"Zhaojie Lyu, Huming Wang, Fang Dai, Yu Lin, Hantao Wen, Xudong Liu, Xiaotong Feng, Zihan Xu, Lei Huang","doi":"10.1007/s00109-025-02543-y","DOIUrl":"https://doi.org/10.1007/s00109-025-02543-y","url":null,"abstract":"<p><p>While zinc finger proteins (ZFPs) are known to be crucial in various cellular activities such as gene expression regulation and energy metabolism, their specific roles in tumor progression are not well-documented. This study focuses on Zinc Finger Protein 83 (ZNF83) to explore its impact on clear cell renal cell carcinoma (ccRCC) and assess its viability as a prognostic biomarker. Public datasets were utilized to analyze ZNF83's expression and functions in ccRCC systematically. Further, in vitro and in vivo experiments were conducted to delve deeper into ZNF83's functional role. Techniques like electron microscopy for mitochondrial morphology and ROS level quantification were used to assess ferroptosis. RNA sequencing and metabolomic mass spectrometry were employed to understand ZNF83's role in oxidative stress modulation and ferroptosis resistance. Our findings demonstrated that ZNF83 overexpression significantly enhanced tumor cell survival and proliferation, while ZNF83 knockout suppressed these processes. Under oxidative stress or upon treatment with ferroptosis inducers, ZNF83 expression was markedly upregulated, and the protein predominantly localized to the cell nucleus. Notably, ZNF83 overexpression conferred resistance to ferroptosis, promoting tumor cell survival under ferroptosis-inducing conditions. Conversely, ZNF83 knockout sensitized cells to ferroptosis, increasing tumor cell death. RNA-seq and metabolomic analyses revealed that ZNF83 is intricately involved in the regulation of NRF2, a master regulator of the antioxidant response, and associated signaling pathways. ZNF83 represents a key ferroptosis regulator in ccRCC, serving as both a promising prognostic biomarker and therapeutic target. Targeting ZNF83 may improve treatment strategies for ccRCC patients. KEY MESSAGES: ZNF83 as a crucial regulator of tumor cell survival and proliferation in renal cancer, a novel discovery in the context of renal cancer progression. ZNF83 overexpression confers resistance to ferroptosis, enhancing tumor cell survival under oxidative stress or ferroptosis-inducing conditions. Utilizing both RNA sequencing and metabolomic mass spectrometry, we provide comprehensive insights into the molecular pathways, particularly NRF2-related, regulated by ZNF83 in ccRCC. ZNF83's potential as a novel prognostic biomarker for ccRCC is proposed, offering a new avenue for personalized treatment strategies and improving treatment outcomes for patients.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":"103 5","pages":"583-597"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036941","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":"Correction to: Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death.","authors":"Saurav Bhowmick, Veera D'Mello, Danielle Caruso, P M Abdul Muneer","doi":"10.1007/s00109-025-02536-x","DOIUrl":"10.1007/s00109-025-02536-x","url":null,"abstract":"","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"489"},"PeriodicalIF":4.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774365","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":"Longitudinal study on immunologic, lipoproteomic, and inflammatory responses indicates the safety of sequential COVID-19 vaccination.","authors":"Jurissa Lang, Andres Bernal, Julien Wist, Siobhon Egan, Sze How Bong, Oscar Millet, Monique Ryan, Aude-Claire Lee, Drew Hall, Philipp Nitschke, Reika Masuda, Allison Imrie, Elaine Holmes, Jeremy Nicholson, Ruey Leng Loo","doi":"10.1007/s00109-025-02527-y","DOIUrl":"10.1007/s00109-025-02527-y","url":null,"abstract":"<p><p>COVID-19 vaccines are crucial in reducing SARS-CoV-2 transmission and severe health outcomes. Despite widespread administration, their long-term systemic effects on human metabolism remain inadequately understood. This longitudinal study aims to evaluate IgG responses, 34 cytokines, 112 lipoproteins, and 21 low-molecular-weight metabolites in 33 individuals receiving two to four COVID-19 vaccine doses. Changes in metabolic profiles for the first 16 days post each dose of vaccine, and up to 480 days post-initial dose, were compared to baseline (before vaccination). Additionally, metabolic profiles of vaccinated participants were compared to a reference cohort of unvaccinated individuals without prior exposure to SARS-CoV-2 infection (controls) and SARS-CoV-2 cases. Positive IgG responses were observed in 78.8% (N = 26) of participants after the first dose, reaching 100% with subsequent doses. The most common side effects were localized pain at the injection site and \"flu-like\" symptoms, reported by > 50% of participants. Systemic side effects, e.g., sore lymph nodes, fatigue, and brain fog, were reported but showed no significant correlations to IgG responses. Transient temporal changes were observed for cytokine IP10 (CXCL10) and glutamic acid around the third vaccine dose. Compared to the reference cohort, 497 vaccinated samples (95.0%) had profiles similar to the controls, while the remaining 26 samples with prior infection exposures were similar to mild cases of SARS-CooV-2 infection. In conclusion, COVID-19 vaccination did not induce lasting changes in inflammatory and metabolic responses, nor did it induce changes similar to mild cases of SARS-CoV-2 infection. This supports the metabolic safety of the vaccine and contributes to increased vaccine confidence. KEY MESSAGES: Minimal changes in inflammatory/metabolic markers up to 480 days post-vaccination. Transient increase in IP10 (CXCL10) and glutamic acid around the third dose. Post-vaccination IgG response did not alter metabolic profiles like SARS-CoV-2 cases. Our findings provide insights into the safety of repeated COVID-19 vaccinations.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"421-433"},"PeriodicalIF":4.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617690","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}

{"title":"FATP1-mediated fatty acid uptake in renal tubular cells as a countermeasure for hypothermia.","authors":"Kie Horioka, Hiroki Tanaka, Shimpei Watanabe, Shinnosuke Yamada, Shuhei Takauji, Akira Hayakawa, Shotaro Isozaki, Keisuke Okaba, Namiko Ishii, Ayumi Motomura, Hiroyuki Inoue, Lynda Addo, Daisuke Yajima, Yoichiro Takahashi, Henrik Druid, Lasse Pakanen, Katja Porvari","doi":"10.1007/s00109-025-02525-0","DOIUrl":"10.1007/s00109-025-02525-0","url":null,"abstract":"<p><p>Hypothermia is a condition in which body temperature falls below 35 °C, resulting from exposure to low environmental temperatures or underlying medical conditions. Postmortem examinations have revealed increased levels of fatty acids in blood and lipid droplet formation in renal tubules during hypothermia. However, the causes and implications of these findings are unclear. This study aimed to analyze the biological significance of these phenomena through lipidomics and transcriptomics analyses of specimens from emergency hypothermia patients and mouse hypothermia models. Both human hypothermia patients and murine models exhibited elevated plasma concentrations of fatty acids and their derivatives compared with controls. Hypothermic mouse kidneys displayed lipid droplet formation, with gene expression analysis revealing enhanced fatty acid uptake and β-oxidation in renal tubular cells. In primary cultured mouse renal proximal tubular cells, low temperatures increased the expression levels of Fatty acid transport protein 1 (FATP1), a fatty acid transporter, and boosted oxygen consumption via β-oxidation. Mice treated with FATP1 inhibitors showed a more rapid decrease in body temperature upon exposure to low temperatures compared with untreated mice. In conclusion, increased fatty acid uptake mediated by FATP1 in renal tubular cells plays a protective role during hypothermia. KEY MESSAGES: Low temperatures increase FATP1 expression and fatty acid uptake in renal proximal tubular cells, resulting in enhanced β-oxidation. Renal proximal tubular cells play an important role in the resistance to hypothermia via lipid uptake. Maintaining renal lipid metabolism is essential for cold stress adaptation.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"403-419"},"PeriodicalIF":4.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558625","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}

{"title":"SMARCC1 promotes M2 macrophage polarization and reduces ferroptosis in lung cancer by activating FLOT1 transcription.","authors":"Youliang Tao, Huafeng Ji, Wensheng Hu, Guojun Jiang, Fangding Yang, Xu Peng, Xu Zhang, Yuqin Yin, Zhize Yuan, Dukai Chen","doi":"10.1007/s00109-025-02531-2","DOIUrl":"10.1007/s00109-025-02531-2","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Grounded on the bioinformatics insights, this study explores the role of flotillin 1 (FLOT1) in modulating macrophage phenotype and immune evasion in lung cancer cells. The bioinformatics analyses revealed positive correlations between FLOT1 expression and infiltration of M2 macrophages, neutrophils, dendritic cells, and CD4 memory T cells. Furthermore, elevated FLOT1 expression was associated with a poor prognosis in lung cancer patients. Analysis of tumor and adjacent non-tumor tissues from 53 lung cancer patients revealed significantly higher immunohistochemical staining of FLOT1 in tumor tissues, showing positive correlation with the staining intensity of PD-L1. Additionally, staining intensities for markers of M2 macrophages (Arg1), CD4 memory T cells (CD4), dendritic cells (CD83), and neutrophils (CD177) were significantly higher in tumor tissues with high FLOT1 levels. Silencing of FLOT1 was induced in two lung cancer cell lines. Co-culturing in conditioned media of the FLOT1-silenced cancer cells led to reduced chemotactic migration and M2 skewing of macrophages in vitro. Using xenograft models, we observed that FLOT1 silencing weakened tumorigenic activity of A549 cells in mice and reduced M2 macrophage infiltration in tumors. SWI/SNF related BAF chromatin remodeling complex subunit C1 (SMARCC1) was identified as a transcription factor that activated FLOT1 transcription by binding to its promoter. Knockdown of SMARCC1 in lung cancer cells similarly reduced the migration and M2 polarization of macrophages as well as weakened tumorigenesis in mice. However, these effects were counteracted by FLOT1 overexpression. Further analysis of the downstream effectors of the SMARCC1/FLOT1 cascade revealed the enrichment of these factors in ferroptosis-related pathways. Mechanistically, SMARCC1 knockdown led to a decreased GSH:GSSG ratio and increased lipid peroxidation in macrophages, while FLOT1 overexpression restored these changes. Transmission electron microscopic observation revealed typical features of ferroptosis-resistant mitochondria following SMARCC1 knockdown, including fragmented or reduced cristae and increased outer membrane integrity. These mitochondrial changes were mitigated by FLOT1 overexpression. In conclusion, SMARCC1 promotes immune evasion in lung cancer by activating FLOT1 transcription. This activation enhances recruitment and M2 polarization of macrophages, and increases PD-L1 expression, reduces ferroptosis. These findings provide valuable insights into the molecular mechanisms of immune evasion and suggest potential therapeutic targets for lung cancer treatment. KEY MESSAGES: • FLOT1 is associated with poor prognosis in lung cancer patients. • Association between FLOT1 and immune cell infiltration in lung cancer. • Silencing FLOT1 inhibits the recruitment of macrophages by lung cancer cells. • SMARCC1 is highly expressed in lung cancer and promotes the transcription of FLOT1. • FLOT1 overexpression rescues the inhibi","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"453-467"},"PeriodicalIF":4.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665235","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":"Evaluation of circulating glypican 4 as a novel biomarker in disease - A comprehensive review.","authors":"A Muendlein, A Leiherer, H Drexel","doi":"10.1007/s00109-025-02520-5","DOIUrl":"10.1007/s00109-025-02520-5","url":null,"abstract":"<p><p>Glypican 4 (GPC4), a member of the cell surface heparan sulfate proteoglycan family, plays a crucial role in regulating various cell signaling and developmental processes. Its ability to be released from the cell surface into the bloodstream through shedding makes it a promising blood-based biomarker in health and disease. In this context, circulating GPC4 has been initially proposed as an insulin-sensitizing adipokine being linked with various conditions of insulin resistance. In addition, serum levels of GPC4 can indicate glycocalyx shedding and associated pathophysiological states, such as systemic inflammation. Particularly in a morbid and elderly population, increased GPC4 concentrations may reflect general organ dysfunction and an advanced state of multimorbidity, showing a strong association with the prognosis of severe conditions such as heart failure or advanced cancer. This comprehensive review is the first to summarize the existing scientific knowledge on the role of circulating GPC4 as a novel diagnostic and prognostic biomarker across different pathologic conditions. We also discuss in detail the putative underlying pathophysiological mechanisms behind these findings.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"355-364"},"PeriodicalIF":4.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442617","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 ferroptosis for the treatment of female reproductive system disorders.","authors":"Rui Ye, Yi-Ming Mao, Yi-Ran Fei, Yue Shang, Ting Zhang, Zhe-Zhong Zhang, Yong-Lin Liu, Jun-Yu Li, Shi-Liang Chen, Yi-Bo He","doi":"10.1007/s00109-025-02528-x","DOIUrl":"10.1007/s00109-025-02528-x","url":null,"abstract":"<p><p>Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical factor in female reproductive health and has been implicated in disorders such as polycystic ovary syndrome, premature ovarian insufficiency, endometriosis, and ovarian cancer. This review explores the intricate molecular mechanisms underlying ferroptosis, emphasizing its reliance on iron metabolism and oxidative stress, which disrupt key processes in reproductive tissues, including granulosa cell function, folliculogenesis, and embryo implantation. Increasing evidence linking ferroptosis to these conditions offers new therapeutic opportunities, with iron chelators, lipid peroxidation inhibitors, and antioxidants showing the potential to alleviate reproductive dysfunction by modulating ferroptotic pathways. In ovarian cancer, ferroptosis inducers combined with conventional cancer therapies, such as chemotherapy, provide promising strategies to overcome drug resistance. This review synthesizes current knowledge on ferroptosis and highlights its importance as a therapeutic target in reproductive health, emphasizing the need for further research to refine and expand treatment options, evaluate their applicability in clinical settings, and explore their role in fertility preservation. By advancing our understanding of ferroptosis regulation, these therapeutic approaches could lead to novel treatments for reproductive disorders and cancers, offering new hope for improving outcomes in women's health and cancer therapy.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"381-402"},"PeriodicalIF":4.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659284","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}