Molecular Neurobiology最新文献

{"title":"Overexpression of TGFBR3 Aggravates Cognitive Impairment and Neuroinflammation by Promoting Microglia M1 Polarization in the APP/PS1 Mouse Model of Alzheimer's Disease.","authors":"Hui Song, Mingyan Xia, Peng Zhao, Jue Yang, Wenfeng Yu","doi":"10.1007/s12035-025-04731-w","DOIUrl":"10.1007/s12035-025-04731-w","url":null,"abstract":"<p><p>Transforming growth factor beta receptor 3 (TGFBR3), also known as betaglycan, is a member of the TGF-β receptor family. In our previous study, bioinformatics analysis revealed that TGFBR3 levels are elevated in patients with Alzheimer's disease (AD) and identified TGFBR3 as a potential risk factor for the disease. However, the precise role of TGFBR3 in the pathogenesis of AD remains largely unclear. In this study, we first validated the elevated levels of TGFBR3 in postmortem brain tissues from AD patients using immunohistochemical staining. Subsequently, gain-of-function experiments and behavioral tests were conducted to explore the functional role of TGFBR3 in the APP/PS1 mouse model. Our findings confirmed that TGFBR3 levels were significantly increased in AD patients compared to normal controls. Overexpression of TGFBR3 in APP/PS1 mice impaired spatial learning and memory abilities and promoted amyloid-β (Aβ) accumulation. Additionally, TGFBR3 overexpression exacerbated neuronal apoptosis and synaptic loss. We also observed that overexpression of TGFBR3 triggered an inflammatory response by promoting microglial polarization to the M1 phenotype, although it had no effect on astrocyte activation. In conclusion, our study demonstrates that increased TGFBR3 levels worsen cognitive impairment and accelerate pathological progression in APP/PS1 mice, suggesting that TGFBR3 could serve as a potential therapeutic target for AD treatment.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7706-7722"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Semaphorin 3A in Hippocampus Alleviates Postpartum Depression-Like Behaviors in Mice.","authors":"Qing Chen, Fang Xu, Hui Wu, Linghua Xie, Hua Li, Cuicui Jiao, Honghai Zhang, Xinzhong Chen","doi":"10.1007/s12035-025-04752-5","DOIUrl":"10.1007/s12035-025-04752-5","url":null,"abstract":"<p><p>Postpartum depression (PPD) is a widespread psychiatric condition affecting up to 20% of postpartum women. Although it is known to be associated with ovarian hormone withdrawal following delivery, current treatments remain limited due to a lack of underlying mechanism. Here, in mice, we identified that semaphorin 3A (sema3A) exhibited a notable increase in expression within the hippocampus of postpartum depression mice, whereas no such upregulation was observed in female mice experiencing depression induced by lipopolysaccharide or chronic restraint stress. The coexpression rate of sema3A and c-Fos was also elevated in the hippocampal CA3 of postpartum depression mice. Importantly, systemic inhibition or genetic knockdown of hippocampal sema3A significantly alleviated the depressive symptoms induced by ovarian hormone withdrawal. Further, overexpression of sema3A in CA3 induced depressive-like behaviors in naïve female mice. In conclusion, our cumulative findings suggest that sema3A in hippocampal CA3 plays a pivotal role in the pathogenesis of postpartum depression, and could serve as a promising treatment target for ameliorating this widespread disorder.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7723-7737"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399531","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":"Genetically Proxied Phosphodiesterase Type 5 (PDE5) Inhibition and Risk of Dementia: A Drug Target Mendelian Randomization Study.","authors":"Stephen O Brennan, Alexander C Tinworth","doi":"10.1007/s12035-025-04732-9","DOIUrl":"10.1007/s12035-025-04732-9","url":null,"abstract":"<p><p>Phosphodiesterase-5 (PDE5) inhibitors have gained interest as a potential treatment for dementia. However, current evidence is limited to observational and pre-clinical studies. We conducted a drug-target Mendelian randomization (MR) analysis to investigate the on-target effects of pharmacological PDE5 inhibition on dementia subtypes and related phenotypes. We selected variants from around the PDE5A locus associated with diastolic and systolic blood pressure, as well as circulating PDE5A levels, to create three instruments for genetically proxied PDE5A inhibition. Using two-sample MR, we validated the instruments against erectile dysfunction and pulmonary arterial hypertension before assessing their associations with dementia subtypes, dementia-related proteins, and neuroimaging traits. After correcting for multiple comparisons, genetically proxied PDE5 inhibition, per one SD lower in diastolic blood pressure, was associated with higher odds of Alzheimer's disease (OR 1.09, 95% CI 1.07-1.11) and Lewy body dementia (OR 1.32, 95% CI 1.23-1.41), but a trend towards lower odds of vascular dementia across all instruments. Genetically proxied PDE5 inhibition was associated with both beneficial and adverse effects on brain MRI traits. This included lower volumes of white matter hyperintensities (SD change - 0.035, 95% CI - 0.025, - 0.045), indicating potential benefits, but also reduced volumes of other structures, including the thalamus, suggesting potential adverse effects. PDE5 inhibition was associated with the concentrations of several proteins implicated in dementia pathophysiology. Our findings suggest that while PDE5 inhibition may be associated with a lower risk of vascular dementia, possibly by preventing white matter hyperintensities, it may increase risk of Alzheimer's disease and Lewy body dementia, warranting further investigation before clinical trials.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7864-7874"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414236","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":"Activation of NR2A-Wnt-TLR2 Signaling Axis in Satellite Glial Cells of the Dorsal Root Ganglion Contributes to Neuropathic Pain Induced by Nerve Injury in Diabetic Mice.","authors":"Yan-Yan Zhang, De-Xin Zhu, Mu-Yun Wang, Ya-Ting Yi, Yu-Heng Feng, Cheng Zhou, Chun-Jie Li, Fei Liu, Jie-Fei Shen","doi":"10.1007/s12035-025-04754-3","DOIUrl":"10.1007/s12035-025-04754-3","url":null,"abstract":"<p><p>Diabetic peripheral neuropathic pain (DPNP), a common diabetic mellitus (DM) complication, may result from the activation of satellite glial cells (SGCs) in the dorsal root ganglion (DRG), potentially enhancing peripheral sensitization. The N-methyl-D-aspartate receptor (NMDAR) subtype NR2A and Toll-like receptor (TLR)2 play key roles in neuroimmune interactions. However, their roles in SGCs of DRG and the precise mechanisms mediating peripheral sensitization in DPNP remain unclear. Here, we found that the expression of glial fibrillary acidic protein (GFAP), NR2A, and TLR2 in SGCs from DRG significantly increased under increased glucose and NMDA stimulation in vitro. Additionally, upregulation of interleukin (IL)-6 and nerve growth factor (NGF) was observed. Notably, lentivirus-induced NR2A knockdown (KD) and C29 (TLR2 inhibitor) significantly blocked the above SGCs changes induced by NMDA and increased glucose. Behavior tests showed mechanical and thermal sensitivities induced by sciatic nerve ligation (SNL) were more obvious in DM background related to streptozotocin (STZ) injection than non-DM background mice, which were significantly alleviated by NR2A conditional knockout (CKO) in SGCs and TLR2 KO. Moreover, immunofluorescence (IF) results revealed the co-expression of NR2A and TLR2 in neurons and SGCs in the DRG. Following SNL in DM mice, the upregulation of NR2A, TLR2, GFAP, β-catenin, p-GSK-3β, p-nuclear factor kappa (NF-κ)-B, IL-6, NGF, Bcl-2-associated X protein (Bax), and Caspase 3, and the significant downregulation of Bcl-2 were consistent with the changes observed after increased glucose and NMDA treatment. The upregulation of TLR2 was blocked by NR2A CKO and Wnt signal pathway inhibition. Additionally, the activation of SGCs, upregulated IL-6 as well as NGF secretion and increased apoptosis, associated with nerve injury in DM background were altered by TLR2 KO and NF-κB pathway inhibition. In conclusion, the activation of the NR2A-Wnt-TLR2 signaling axis mediated peripheral sensitization in the DRG by influencing SGCs' activation, and the synthesis and secretion of pro-inflammatory cytokines and NGF, promoting SGCs' apoptosis, thus exacerbating a peripheral nerve injury related-NP in DM background. Our study provided insights into the role of NR2A-Wnt-TLR2 signaling axis of SGCs in mediating the generation and maintenance of DPNP and suggested targeting this signaling axis may be a promising therapeutic approach for DPNP.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8013-8037"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JZL-184 Alleviate Neurological Impairment through Regulation of Mitochondrial Transfer and Lipid Droplet Accumulation after Cardiac Arrest.","authors":"Qiang Zhang, Chenyu Zhang, Yuanzheng Lu, Haohong Zhan, Bo Li, Hongyan Wei, Yilin Yang, Liaoxing Liao, Chao Lan, Chunlin Hu","doi":"10.1007/s12035-024-04633-3","DOIUrl":"10.1007/s12035-024-04633-3","url":null,"abstract":"<p><p>Astrocytes are abundant glial cells in the central nervous system (CNS) that play important roles in brain injury following cardiac arrest (CA). Following brain ischemia, astrocytes trigger endogenous neuroprotective mechanisms, such as fatty acid transport. Lipid droplets (LDs) are cellular structures involved in neutral lipid storage and play essential roles in many biological processes. However, whether lipid droplet metabolism is related to the neurological prognosis after CA remains unclear. JZL-184 is a selective irreversible inhibitor of monoacylglycerol lipase (MAGL), and previous investigations revealed that JZL-184 confers neuroprotection in the brain following stroke. However, further investigations are warranted to explore the effect and mechanism of JZL-184 after CA. Here, we reveal that JZL-184 is neuroprotective after cardiac arrest, as it alleviates astroglial activation by upregulating the expression of transforming growth factor beta 1 (TGF-β1), promotes the transfer of mitochondria from astrocytes to neurons in the astrocyte‒neuron coculture system, and reduces lipid droplet accumulation in neurons. Mechanistically, this protective effect depends on the downstream genes DUSP4 and Rab27b. This study provides additional insights into strategies for inhibiting neurological impairment and suggests a potential therapeutic target after cardiac arrest.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7093-7109"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Interplay Between the Nrf2/Keap1/HO-1/SIRT-1 Pathway and the p75NTR/PI3K/Akt/MAPK Cascade in Neurological Disorders: Mechanistic Insights and Therapeutic Innovations.","authors":"Ritam Mukherjee, Ravi Rana, Sidharth Mehan, Zuber Khan, Ghanshyam Das Gupta, Acharan S Narula, Rajaram Samant","doi":"10.1007/s12035-025-04725-8","DOIUrl":"10.1007/s12035-025-04725-8","url":null,"abstract":"<p><p>Neurological illnesses are debilitating diseases that affect brain function and balance. Due to their complicated aetiologies and progressive nature, neurodegenerative and neuropsychiatric illnesses are difficult to treat. These incurable conditions damage brain functions like mobility, cognition, and emotional regulation, but medication, gene therapy, and physical therapy can manage symptoms. Disruptions in cellular signalling pathways, especially those involving oxidative stress response, memory processing, and neurotransmitter modulation, contribute to these illnesses. This review stresses the interplay between key signalling pathways involved in neurological diseases, such as the Nrf2/Keap1/HO-1/SIRT-1 axis and the p75NTR/PI3K/Akt/MAPK cascade. To protect neurons from oxidative damage and death, the Nrf2 transcription factor promotes antioxidant enzyme production. The Keap1 protein releases Nrf2 during oxidative stress for nuclear translocation and gene activation. The review also discusses how neurotrophin signalling through the p75 neurotrophin receptor (p75NTR) determines cell destiny, whether pro-survival or apoptotic. The article highlights emerging treatment approaches targeting these signalling pathways by mapping these connections. Continued research into these molecular pathways may lead to new neurological disease treatments that restore cellular function and neuronal survival. In addition to enhanced delivery technologies, specific modulators and combination therapies should be developed to fine-tune signalling responses. Understanding these crosstalk dynamics is crucial to strengthening neurological illness treatment options and quality of life.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7597-7646"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Alterations in Core Subunits of Mitochondrial Complex I and Their Relation to Parkinson's Disease.","authors":"Matheus Caetano Epifane-de-Assunção, Ana Gabrielle Bispo, Ândrea Ribeiro-Dos-Santos, Giovanna C Cavalcante","doi":"10.1007/s12035-024-04526-5","DOIUrl":"10.1007/s12035-024-04526-5","url":null,"abstract":"<p><p>Among the myriad of neurodegenerative diseases, mitochondrial dysfunction represents a nexus regarding their pathogenic processes, in which Parkinson's disease (PD) is notable for inherent vulnerability of the dopaminergic pathway to energy deficits and oxidative stress. Underlying this dysfunction, the occurrence of defects in complex I (CI) derived from molecular alterations in its subunits has been described in the literature. However, the mechanistic understanding of the processes mediating the occurrence of mitochondrial dysfunction mediated by CI deficiency in PD remains uncertain and subject to some inconsistencies. Therefore, this review analyzed existing evidence that may explain the relationship between molecular alterations in the core subunits of CI, recognized for their direct contribution to its enzymatic performance, and the pathogenesis of PD. As a result, we discussed 47 genetic variants in the 14 core subunits of CI, which, despite some discordant results, were predominantly associated with varying degrees of deficiency in complex enzymatic activity, as well as defects in supercomplex biogenesis and CI itself. Finally, we hypothesized about the relationship of the described alterations with the pathogenesis of PD and offered some suggestions that may aid in the design of future studies aimed at elucidating the relationship between such alterations and PD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"6968-6982"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NEFL Modulates NRN1-Mediated Mitochondrial Pathway to Promote Diacetylmorphine-Induced Neuronal Apoptosis.","authors":"Sensen Zhu, Liping Su, Mengjie Zhuang, Li Liu, Min Ji, Jingyu Liu, Chenlu Dai, Jinling Xiao, Yaling Guan, Long Yang, Hongwei Pu","doi":"10.1007/s12035-024-04629-z","DOIUrl":"10.1007/s12035-024-04629-z","url":null,"abstract":"<p><p>Diacetylmorphine abuse is a major social problem that jeopardizes the world, and abuse can cause serious neurological disorders. Apoptosis plays an important role in neurological diseases. A previous study by our group found that the brain tissue of diacetylmorphine-addicted rats showed severe vacuole-like degeneration and increased apoptosis, but the exact mechanism has not yet been reported. We used TMT technology to sequence the diseased brain tissue of rats, and selected neurofilament light chain (NEFL) and neuritin (NRN1) as the focus of our research. We explore the possible roles and mechanisms played by both. Based on the construction of apoptotic cell model, we used overexpression/silencing lentiviral vectors to interfere with the expression of NEFL in PC12 cells, and the results suggested that NEFL could regulate NRN1 to affect the apoptosis level. To further understand the specific mechanism, we used transmission electron microscopy to observe the ultrastructure of apoptotic cells, and the results showed that compared with the control group, mitochondria in the model group showed obvious vacuolation as well as expansion, a significant increase in the accumulation of ROS, and a significant decrease in the mitochondrial membrane potential; after overexpression/silencing of NEFL, these changes were found to occur along with the alteration of NEFL expression. In summary, we conclude that diacetylmorphine induces neuronal apoptosis, and the specific mechanism is that NEFL regulates the NRN1-mediated mitochondrial pathway to promote apoptosis.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"6983-6997"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667548","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":"Central Nervous System Response Against Ionizing Radiation Exposure: Cellular, Biochemical, and Molecular Perspectives.","authors":"Ravi Kumar, Pratibha Kumari, Raj Kumar","doi":"10.1007/s12035-025-04712-z","DOIUrl":"10.1007/s12035-025-04712-z","url":null,"abstract":"<p><p>Gamma radiation is known to induce several detrimental effects on the nervous system. The hippocampus region, specifically the dentate gyrus (DG) and subventricular zone (SVZ), have been identified as a radiation-sensitive neurogenic niche. Radiation alters the endogenous redox status of neural stem cells (NSCs) and other proliferative cells, especially in the hippocampus region, leading to oxidative stress, neuroinflammation, and cell death. Planned (i.e., radiotherapy of brain tumor patients) or unplanned radiation exposure (i.e., accidental radiation exposure) can induce nonspecific damage to neuronal tissues, resulting in chronic or acute radiation syndrome. Although anatomical alterations in the neuronal tissues have been reported at higher doses of gamma radiation, biochemical and molecular perturbations may be evident even at much lower radiation doses. They may manifest in the form of neuronal deficits and cognitive impairment. In the present review, several molecular events and signaling pathways, such as oxidative stress, neuroinflammation, apoptosis, cognition, neuroplasticity, and neurotoxicity induced in neuronal cells upon ionizing radiation exposure, are reviewed. Furthermore, brain-specific radioprotectors and mitigators that protect normal neuronal cells and tissues against ionizing radiation during radiotherapy of cancer patients or nuclear emergencies are also discussed.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7268-7295"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum Inflammatory Factors Levels and Risk of Myasthenia Gravis: A Bidirectional Mendelian Randomization Study.","authors":"Sun Jingjing, Huo Liang, Yu Tao","doi":"10.1007/s12035-025-04744-5","DOIUrl":"10.1007/s12035-025-04744-5","url":null,"abstract":"<p><p>Myasthenia gravis (MG) is an autoimmune disorder characterized by muscle weakness, where the role of inflammatory processes remains incompletely understood. Bidirectional Mendelian randomization (MR) provides a method to explore potential causal relationships between traits. In this bidirectional MR study, we investigated the relationship between 40 serum inflammatory factors and MG using the two-sample MR approach. The inverse variance weighted (IVW) method was the primary analytical method. Factors with P < 0.05 after false discovery rate (FDR) correction were considered to have a significant causal relationship with MG. Bayesian colocalization and functional mapping were employed to further analyze the instrumental variables. We then used reverse MR to examine potential reverse causality and validated these findings in the UK Biobank-PPP cohort. A phenome-wide association study (PheWAS) was conducted using UK Biobank and FinnGen data to evaluate the potential side effects of targeting these inflammatory factors as therapeutic interventions. Our results indicated that elevated levels of serum interleukin-10 (IL-10) were associated with a decreased risk of MG (P = 9.34E-03, OR [95% CI] = 0.52 [0.33-0.85]). Reverse MR revealed no evidence of reverse causality (P > 0.05), with further validation in the UK Biobank-PPP cohort (P = 3.81E-3, OR [95% CI] = 5.43E-02 [7.54E-03-3.91E-01]). The PheWAS outcomes showed associations of serum IL-10 levels across a broad phenotypic spectrum. Our findings suggest that IL-10 may play a protective role in the pathogenesis of MG. The absence of reverse causality highlights IL-10 as a potential therapeutic target. This study emphasizes the importance of inflammatory factors in autoimmune disorders and supports the utility of MR studies in uncovering novel therapeutic targets.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7738-7746"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}