Molecular Medicine最新文献

{"title":"USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer.","authors":"Zhiyong Wang, Cheng Yu, Gengchen Xie, Kaixiong Tao, Zhijie Yin, Qing Lv","doi":"10.1186/s10020-025-01182-w","DOIUrl":"https://doi.org/10.1186/s10020-025-01182-w","url":null,"abstract":"<p><strong>Background: </strong>Mitophagy, essential for cellular homeostasis, is involved in eliminating damaged mitochondria and is associated with cancer progression and chemoresistance. The specific impact of mitophagy on microsatellite instability-high (MSI-H) colorectal cancer (CRC) is still under investigation. Ubiquitination, a post-translational modification, is essential for controlling protein stability, localization, and function. This study identifies USP14, a deubiquitinating enzyme, as a key regulator of mitophagy in MSI-H CRC.</p><p><strong>Methods: </strong>A deubiquitinating enzyme (DUBs) siRNA library screening identified USP14 as a key regulator of mitophagy. Tissue samples from patients were analyzed using immunohistochemistry and Western blot. USP14 knockdown cell lines were generated using lentiviral transfection. Protein interactions between USP14 and BAG4 were confirmed by co-immunoprecipitation, while quantitative PCR was used to measure gene expression. Mitochondrial proteins were extracted to analyze mitophagy, and flow cytometry was used to assess apoptosis. Finally, a mouse xenograft model was employed to study USP14's role in tumor growth and oxaliplatin sensitivity.</p><p><strong>Results: </strong>Screening reveals that USP14 inhibits mitophagy and CRC (MSI-H) show high USP14 expression which correlates with poor prognosis. Functional analyses reveal that knocking down USP14 reduces tumor growth, and increases sensitivity to oxaliplatin. Mechanically, USP14 inhibits mitophagy by K48-deubiquitinating and stabilizing BAG4 at K403, which prevents the recruitment of Parkin to damaged mitochondria. The significant clinical relevance of USP14, BAG4, and PRKN are proved in tumor tissues.</p><p><strong>Conclusions: </strong>The study highlights the USP14/BAG4/PRKN axis as a critical pathway in CRC (MSI-H), suggesting that targeting USP14 could inhibit tumor progression and improve chemotherapeutic outcomes. These findings underscore the importance of ubiquitination and mitophagy in cancer biology, indicating a potential therapeutic target for MSI-H CRC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"163"},"PeriodicalIF":6.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035710","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":"BACH1 deficiency improves placental angiogenesis via SLC25A51-mediated mitochondrial NAD⁺ transport in intrahepatic cholestasis of pregnancy.","authors":"Shengpeng Li, Weiying Zhu, Zhixuan Xing, Dan Chen, Huimin Zhao, Yanli Zhang, Wenlong Zhang, Jiaojiao Sun, Yaxian Wu, Ling Ai, Qingfeng Pang","doi":"10.1186/s10020-025-01215-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01215-4","url":null,"abstract":"<p><strong>Background: </strong>Placental angiogenesis is particularly important in the treatment of intrahepatic cholestasis of pregnancy (ICP). Although BACH1 has been implicated in angiogenesis associated with cardiovascular diseases, its specific role and underlying mechanisms in ICP remain unclear. This study aims to investigate the role of BACH1 in ICP.</p><p><strong>Methods: </strong>The study used clinical samples and two distinct mouse models of ICP to validate BACH1 alterations in ICP through immunohistochemistry (IHC), immunofluorescence (IF), and western blot (WB) analyses. Subsequently, global BACH1-knockout mice were employed to investigate the phenotypic effects of BACH1 deficiency on ICP progression. The molecular mechanisms underlying the regulatory role of BACH1 in ICP were further elucidated using multi-omics approaches (e.g., transcriptomics and proteomics), combined with dual-luciferase reporter assays and electrophoretic mobility shift assays (EMSA).</p><p><strong>Results: </strong>The expression of BACH1 was significantly upregulated in ICP, and its expression level positively correlated with clinicopathological indicators of ICP. Experiments using BACH1-knockout mice demonstrated that BACH1 deletion effectively ameliorated ICP-related placental tissue damage and significantly enhanced the expression levels of angiogenesis markers such as vascular endothelial growth factor (VEGF). Mechanistic investigations indicated that BACH1 deficiency activated the transcriptional expression of solute carrier family 25 member 51 (SLC25A51), thereby promoting the mitochondrial transport of nicotinamide adenine dinucleotide (NAD⁺), restoring mitochondrial function, and improving the activities of electron transport chain complexes I, II, and IV. Notably, BACH1 deficiency promoted taurocholic acid (TCA)-induced proliferation of human umbilical vein endothelial cells (HUVECs), whereas this phenotype could be reversed by shRNA-mediated knockdown of SLC25A51. Further studies confirmed that administration of the specific BACH1 inhibitor HPPE effectively alleviated TCA-induced suppression of HUVECs proliferation.</p><p><strong>Conclusions: </strong>BACH1 may suppress placental angiogenesis by inhibiting the transcriptional expression of SLC25A51, making it a potential therapeutic target. Specifically, pharmacological inhibition of BACH1 could provide a targeted therapeutic strategy for placental angiogenesis associated with ICP.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"162"},"PeriodicalIF":6.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982401","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":"Innate immune training in the neonatal response to sepsis.","authors":"Jaimar C Rincon, Dayuan Wang, Valerie E Polcz, Evan L Barrios, Marvin L Dirain, Ricardo F Ungaro, Dina C Nacionales, Leilani Zeumer-Spataro, Feifei Xiao, Philip A Efron, Lyle L Moldawer, Guoshuai Cai, Shawn D Larson","doi":"10.1186/s10020-025-01179-5","DOIUrl":"https://doi.org/10.1186/s10020-025-01179-5","url":null,"abstract":"<p><p>Neonates, especially those born prematurely, are highly vulnerable to infection-induced mortality. Numerous observational and immunological studies in newborns have shown that live attenuated vaccines have beneficial, non-specific effects (NSEs) against secondary infections to unrelated pathogens. These beneficial effects have been attributed to trained immunity, and emergency granulopoiesis plays an essential role. However, trained immunity has been shown to affect multiple myeloid subsets and how trained immunity influences the host protective response is still undefined. Here we show that Bacillus-Calmette-Guérin (BCG) vaccination improves survival to polymicrobial sepsis by simultaneously reprogramming broad aspects of myelopoiesis. Specifically, BCG vaccination expands multiple myeloid subsets, including the lineage (Lin)^-Sca- 1⁺c-kit⁺ (LSK) and granulocytic-macrophage progenitors (GMPs), and increases CD11b⁺Gr1⁺ cell number, as well as their oxidative metabolism and capacity to stimulate T-cell proliferation in response to sepsis. Single-cell RNA sequencing of neonatal splenocytes suggests that BCG-vaccination changes the broad transcriptional landscape of multiple myeloid subsets. The result is the maturation of various neutrophil and monocyte subsets, stimulation of antimicrobial processes, and suppression of inflammatory pathways and myeloid-derived suppressor cell transcription. These findings reveal that BCG administration early after birth fundamentally reorganizes the myeloid landscape to benefit the subsequent response to polymicrobial infection.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"159"},"PeriodicalIF":6.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018898","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":"Surfactant protein D alleviates chondrocytes senescence by upregulating SIRT3/SOD2 pathway in osteoarthritis.","authors":"Huanyu Jiang, Yantao Zhang, Piyao Ji, Jianghua Ming, Yaming Li, Yan Zhou","doi":"10.1186/s10020-025-01221-6","DOIUrl":"https://doi.org/10.1186/s10020-025-01221-6","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is an age-related degenerative disease that affects bones and joints. The hallmark pathogenesis of OA is associated with chondrocyte senescence. Surfactant protein D (SP-D) is a member of the innate immune proteins family, which can inhibit the immune inflammatory response of chondrocytes. However, the effect of SP-D on chondrocyte senescence phenotype is poorly studied. The present study investigated the phenotypic regulation of OA chondrocyte senescence mediated by SP-D and explored the underlying molecular mechanism.</p><p><strong>Methods: </strong>In this study, an in vitro senescence chondrocyte model was generated by subjecting chondrocytes to IL-1β treatment. Furthermore, the expression of aging-related biomarkers and mitochondrial functions in SP-D overexpressing chondrocytes was observed. Co-immunoprecipitation was conducted to verify the association between SP-D and the identifed proteins within chondrocytes. Moreover, a rat OA model was established by destabilization of the medial meniscus surgery, and the effect of SP-D on reversing the aging phenotype of OA cartilage was investigated.</p><p><strong>Results: </strong>The results indicated that SP-D significantly decreased senescence and enhanced mitochondrial functions in senescent chondrocytes. The RNA-sequencing analysis revealed that the SIRT3/SOD2 pathway predominantly modulated the effect of SP-D on alleviating senescence. In addition, SP-D overexpression mitigated chondrocyte senescence, suppressed senescence-associated secretory phenotype (SASP) secretion and ameliorated mitochondrial damage. In the rat OA model, SP-D inhibited aging-related pathological changes by upregulating SIRT3/SOD2 pathway, thereby protecting the cartilage tissue integrity.</p><p><strong>Conclusion: </strong>These findings indicate that SP-D modulates the inhibition of chondrocyte senescence by upregulating SIRT3/SOD2 pathway. These data indicate that targeting SP-D and the SIRT3/SOD2 pathway might be a promising therapeutic strategy for OA.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"161"},"PeriodicalIF":6.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011658","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":"TMSB10 drives prostate cancer aggressiveness via immune microenvironment regulation.","authors":"Haoran Xia, Jiaxin Ning, Xiaoxiao Guo, Hongchen Song, Xuanhao Li, Xuan Wang","doi":"10.1186/s10020-025-01211-8","DOIUrl":"https://doi.org/10.1186/s10020-025-01211-8","url":null,"abstract":"<p><p>Thymosin β10 (TMSB10) has emerged as a key player in the progression of prostate cancer, significantly influencing the tumor immune microenvironment. Pan-cancer analysis from The Cancer Genome Atlas (TCGA) revealed that TMSB10 is upregulated across multiple cancer types, particularly in prostate cancer, where high TMSB10 expression correlates with poorer patient outcomes. Functional assays using prostate cancer cell lines LNCaP and DU145 showed that TMSB10 silencing suppresses cell proliferation, migration, and invasion, while overexpression enhances these oncogenic processes. Furthermore, co-culture experiments demonstrated that TMSB10 overexpression skews macrophage polarization, decreasing the population of M1-type macrophages while increasing M2-type macrophages. This shift reduces immune cell cytotoxicity and alters cytokine secretion, highlighting TMSB10's role in immune evasion. These findings establish TMSB10 as a pivotal factor in prostate cancer biology, promoting tumor aggressiveness and modulating the immune response within the tumor microenvironment. TMSB10 presents a promising therapeutic target for prostate cancer, offering new avenues for treatments aimed at altering the tumor immune landscape. This research also provides a foundation for further exploration of TMSB10's role in other cancers.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"160"},"PeriodicalIF":6.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033429","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":"Exogenous TSG-6 treatment alleviates DSS-induced colitis in mice by modulating Pou2f3 and promoting tuft cells differentiation.","authors":"Shaopeng Yang, Yuqi Li, Rongwei Ruan, Jiangping Yu, Bo Zhu, Haibin Lou, Xiaolan Zhang, Shi Wang","doi":"10.1186/s10020-025-01230-5","DOIUrl":"https://doi.org/10.1186/s10020-025-01230-5","url":null,"abstract":"<p><strong>Background: </strong>Whereas intestinal epithelial barrier dysfunction is implicated in inflammatory bowel disease (IBD), the underlying mechanisms remain elusive. Tumor necrosis factor α stimulated gene 6 (TSG-6) is a secretory protein with anti-inflammatory properties. Our previous research demonstrated TSG-6 can relieve intestinal inflammation and mucosal damage. However, the underlying mechanism and targets remain unclear. This research sought to explore how TSG-6 regulates the intestinal epithelial barrier and its mechanistic role in experimental colitis.</p><p><strong>Methods: </strong>IBD mouse model was generated using dextran sodium sulfate (DSS), with or without intraperitoneal injection of TSG-6(100 µg/kg or 200 µg/kg). The effects of TSG-6 on colonic inflammation and intestinal barrier function were investigated. Label-free quantitative proteomic analysis was performed on intestinal samples to explore the mechanism and therapeutic target of TSG-6. Molecular interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence colocalization.</p><p><strong>Results: </strong>TSG-6 treatment significantly attenuated DSS-induced colitis symptoms and inflammatory cell infiltration. Microarray analysis revealed that TSG-6 decreased pro-inflammatory cytokine levels in colon tissue. TSG-6 restored the intestinal epithelial barrier through the promotion of intestinal epithelial cells (IECs) proliferation and mitigation of tight junctions (TJs) damage. Mechanistically, TSG-6 promoted tuft cells differentiation and increased interleukin-25 (IL-25) levels by directly binding to Pou class 2 homeobox 3(Pou2f3) and up-regulating its expression in the gut.</p><p><strong>Conclusions: </strong>This study demonstrated TSG-6 as a positive regulator of tuft cells differentiation by interacting with Pou2f3, and the effectiveness of exogenous TSG-6 treatment on maintaining intestinal barrier integrity showed a promising potential for its clinical application.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"157"},"PeriodicalIF":6.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008786","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":"Preclinical evaluation of AAV9-coSMN1 gene therapy for spinal muscular atrophy: efficacy and safety in mouse models and non-human primates.","authors":"Wenhao Ma, Zhijie Wu, Tianyi Zhao, Yan Xia, Jing Qin, Xue Tian, Xin Li, Jun He, Yan Zhang, Lina Zhang, Li Li, Zheyue Dong, Zhichun Feng, Xiaoyan Dong, Wang Sheng, Xiaobing Wu","doi":"10.1186/s10020-025-01207-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01207-4","url":null,"abstract":"<p><strong>Background: </strong>Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by the loss of motor neurons in the spinal cord. Our team has initiated clinical trials using adeno-associated virus serotype 9 (AAV9) vectors carrying a codon-optimized human SMN1 (coSMN1) gene, delivered via intrathecal (IT) injection. Here, we present the preclinical research that laid the groundwork for these trials, offering comprehensive data on the efficacy and safety of AAV9-coSMN1 in both murine models and non-human primates.</p><p><strong>Material and method: </strong>We developed a codon-optimized hSMN1 expression cassette and analyzed SMN protein levels using Western blot and immunofluorescence. Taiwanese SMA-like mouse model was employed to assess tail length preservation, as well as to examine motor neuron and skeletal muscle pathological phenotypes through immunofluorescence and histopathological staining. Serum biomarkers in both mice and cynomolgus monkeys were measured using a blood chemistry analyzer. The in-vivo biodistribution of AAV9-coSMN1 and toxicological profile were investigated through quantitative Polymerase Chain Reaction(qPCR) and histopathological staining.</p><p><strong>Results: </strong>Codon optimization of hSMN1 led to enhanced gene expression and increased SMN protein levels in vitro. AAV9-coSMN1 demonstrated significant therapeutic efficacy in a Type 3 SMA mouse model, effectively rescuing motor neurons, preserving tail integrity, and improving skeletal muscle histopathology. In vivo studies, both mice and cynomolgus monkeys revealed widespread CNS distribution following a single intracerebroventricular or intrathecal injection, with no observed toxic inflammatory responses in the dorsal root ganglia. Peripheral organs also showed detectable levels of the vector gene, indicating effective systemic distribution.</p><p><strong>Conclusion: </strong>The preclinical evaluation confirms that AAV9-coSMN1 is a safe and effective therapeutic candidate for SMA, with potential applicability across various phenotypes. The study provides critical data supporting its advancement to clinical trials, underscoring its promise for broader neurological applications.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"158"},"PeriodicalIF":6.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033781","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":"Correction: S-propargyl-cysteine attenuates temporomandibular joint osteoarthritis by regulating macrophage polarization via Inhibition of JAK/STAT signaling.","authors":"Wenyi Cai, Antong Wu, Zhongxiao Lin, Wei Cao, Janak L Pathak, Richard T Jaspers, Rui Li, Xin Li, Kaihan Zheng, Yufu Lin, Na Zhou, Xin Zhang, Yizhun Zhu, Qingbin Zhang","doi":"10.1186/s10020-025-01214-5","DOIUrl":"https://doi.org/10.1186/s10020-025-01214-5","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"156"},"PeriodicalIF":6.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008106","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":"PYK2 promotes cell proliferation and epithelial-mesenchymal transition in endometriosis by phosphorylating Snail1.","authors":"Lu Liu, Lan Liu, Chenjing Yue, Shiyu Du, Jiayu Liu, Zhenhai Yu","doi":"10.1186/s10020-025-01218-1","DOIUrl":"https://doi.org/10.1186/s10020-025-01218-1","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Endometriosis can lead to decreased endometrial receptivity, reduced rates of implantation, and diminished ovarian reserve. Currently, more than 50% of infertile women are found to suffer from endometriosis. However the etiology and pathogenesis of endometriosis are still poorly understood. Epithelial-mesenchymal transition (EMT) has been confirmed to be involved in endometriosis. PYK2 is a non-receptor tyrosine kinase that affects cell proliferation, survival, and migration by regulating intracellular signaling pathways. PYK2 plays a regulatory role in the EMT process by affecting the expression of genes associated with EMT through the influence of transcription factors. Snail1 (Snail1) plays a key role in the EMT process and is highly expressed in endometriosis tissues. On the other hand, Snail1 affects the invasive and metastatic ability of endometriosis cells mainly by regulating the EMT process. However, the upstream mechanisms that regulate the process of Snail1 protein stability in endometriosis are not clear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We identified a non-receptor tyrosine kinase, proline-rich tyrosine kinase 2 (PYK2 or PTK2B), and examined the expression of PYK2 in endometriosis. The relevant plasmids were constructed. This study enrolled 20 patients with laparoscopically confirmed endometriosis meeting ASRM diagnostic criteria, collecting ectopic lesions (14 ovarian endometriotic cysts and 6 deep infiltrating nodules) along with matched eutopic endometrial tissues (15 proliferative phase, 5 secretory phase) as controls. All tissue specimens underwent immunohistochemical analysis. Human endometrial stromal cells (HESC) were isolated from normal endometrium of 3 control patients for in vitro meconium induction. Ectopic endometrial stromal cells (EESC) were obtained from 5 ectopic lesions. Protein extracts from both ectopic tissues and cells were subjected to Western blot and co-immunoprecipitation (Co-IP) interaction validation. Functional assays (proliferation/migration/invasion) were performed using EESC and 11Z cell lines with triplicate biological replicates. Co-IP experiments were performed to verify the interaction between PYK2 and Snail1, as well as to determine the specific location of this interaction. Additionally, we examined the effect of PYK2 on endometriosis cells in vitro and whether VS-6063 inhibits the biological functions of endometriosis cells. Endometriosis models were established in 20 five-week-old female C57BL/6 mice, randomly allocated into experimental (n = 10) and control (n = 10) groups. Statistical analyses were conducted using GraphPad Prism 7.0, employing parametric tests for normally distributed data and non-parametric methods otherwise, with Benjamini-Hochberg correction for multiple comparisons.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;PYK2 is highly expressed in endometriosis tissues. It acts as a new binding partner of Snail1 and enhances EMT in endometriosis by increasing the","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"155"},"PeriodicalIF":6.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034241","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 interplay of iron, oxidative stress, and α-synuclein in Parkinson's disease progression.","authors":"Yan Chen, Xixi Luo, Yukun Yin, Elizabeth Rosalind Thomas, Kezhi Liu, Wenjun Wang, Xiang Li","doi":"10.1186/s10020-025-01208-3","DOIUrl":"https://doi.org/10.1186/s10020-025-01208-3","url":null,"abstract":"<p><p>The irreversible degeneration of dopamine neurons induced by α-synuclein (α-syn) aggregation in the substantia nigra is the central pathological feature of Parkinson's disease (PD). Neuroimaging and pathological autopsy studies consistently confirm significant iron accumulation in the brain of PD patients, suggesting a critical role for iron in disease progression. Current research has established that iron overload induces ferroptosis in dopaminergic neurons, evidence indicates that the impact of iron on PD pathology extends beyond ferroptosis. Iron also plays a regulatory role in modulating α-syn, affecting its aggregation, spatial conformation, post-translational modifications, and mRNA stability. Iron-induced α-syn aggregation can contribute to dopaminergic neurodegeneration through additional mechanisms, potentially creating a feedback loop in which α-syn further enhances iron accumulation, thus perpetuating a vicious cycle of neurotoxicity. Given α-syn's intrinsically disordered structure, targeting iron metabolism presents a promising therapeutic strategy for PD. Therefore, the development of iron chelators, alone or in combination with other therapeutic drugs, may offer a beneficial approach to alleviating PD symptoms and slowing disease progression.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"154"},"PeriodicalIF":6.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033701","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}