Molecular Medicine最新文献

{"title":"Kynu inhibition mitigates bile duct ischemic injury by rewiring tryptophan metabolism to restore tight junction integrity.","authors":"Guoqing Bao, Siliang Zhang, Zhengchen Ye, Ding Luo, Pinduan Bi, Bin Yang","doi":"10.1186/s10020-025-01310-6","DOIUrl":"10.1186/s10020-025-01310-6","url":null,"abstract":"<p><strong>Background: </strong>Disruption in bile duct barrier function contributes to hepatocyte toxicity in ischemia-reperfusion injury, often leading to surgical complications in liver resection, transplantation, and hemorrhagic shock. However, the underlying mechanisms remain incompletely understood.</p><p><strong>Methods: </strong>Transcriptomic and proteomic analyses were conducted to examine tryptophan (Trp) metabolism in a Pringle maneuver-induced bile duct injury rat model; Hypoxia/Reoxygenation (H/R) was used to establish an in vitro cholangiocyte injury model. Cholangiocyte injury was assessed via hematoxylin and eosin (H&E) staining, Ki67/myeloperoxidase (MPO) immunohistochemistry, transmission electron microscopy (TEM), and TUNEL/CK19 co-staining. Tight junction integrity was evaluated by measuring transepithelial electrical resistance (TEER), inulin permeability, and confocal immunofluorescence (IF) for ZO-1/CK19 co-staining. Gene expression was quantified using RT-qPCR and Western blotting, while metabolites were analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS).</p><p><strong>Results: </strong>Significant alterations in Trp metabolism-related genes (Kynu, Haao, Kat1/Kat2) and metabolites were observed. Continuous Pringle maneuver resulted in elevated levels of 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA), a decreased xanthurenic acid (XA) level. In vitro, Kynu inhibition, using shRNA or the inhibitor benserazide (BSZ), ameliorated tight junction impairment and attenuated inflammatory damage in hypoxic biliary epithelial cells. In vivo, post-ischemia Kynu blockade reduced bile duct damage, inflammation, and biliary barrier permeability. Proteome analysis revealed that Kynu inhibition decreased 3-HAA, AA and QA levels while increased XA level. Notably, XA (but not AA or QA) treatment restored cell junction integrity under hypoxic conditions and modulated cytokine expression, potentially via ZO1 regulation through the GluR2/CX50 pathway. By day 7, BSZ or XA administration reduced serum bilirubin levels and mitigated of bile duct hyperplasia.</p><p><strong>Conclusion: </strong>Our findings demonstrated that Kynu inhibition alleviates bile duct ischemic injury by reprogramming dysregulated tryptophan metabolism, particularly through XA upregulation. This modulation may restore tight junction function via the GluR2/3/CX50-ZO1 axis, thereby preserving blood-biliary barrier integrity. Targeting Kynu represents a promising therapeutic strategy for ischemia-induced bile duct injury.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"279"},"PeriodicalIF":6.4,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883202","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":"POC1A induces epithelial-mesenchymal transition to promote growth and metastasis through the STAT3 signaling pathway in triple-negative breast cancer.","authors":"Yuzhou Qian, Yu Che, Shanqi Li, Xue Zhang, Qingshu Li, Yong Zhu, Long Wang, Xuedong Yin","doi":"10.1186/s10020-025-01315-1","DOIUrl":"10.1186/s10020-025-01315-1","url":null,"abstract":"<p><strong>Objectives: </strong>Triple-negative breast cancer (TNBC) is known for its aggressiveness, which can be attributed to its heterogeneity, metastasis, and invasion capabilities. POC1 centriolar protein homolog A (POC1A), a centriolar protein involved in the formation of stable centrioles, has been associated with both cancer promotion and suppression in various malignant tumors. However, the underlying mechanisms that drive POC1A-induced metastases in TNBC remain to be elucidated.</p><p><strong>Methods: </strong>The expression of POC1A changes and their clinical significance have been evaluated using TNBC tissues and a database. POC1A expression was examined in clinical samples and cells. The impacts of POC1A on the epithelial-mesenchymal transition's (EMT) relative factor expression was examined using immunofluorescence (IF), transcription-quantitative PCR (RT-qPCR), and Western blotting. We investigated the migration and invasion capabilities of TNBC cells and found that the patterns of tumor growth and metastasis varied correspondingly in different xenograft models. RNA sequencing (RNA-seq) was performed to explore the signaling pathways involved in POC1A, which was verified by several experiments.</p><p><strong>Results: </strong>Our study identified an increase in the expression of POC1A in TNBC tissues, which was found to correlate with tumor size and lymph node metastasis. Meanwhile, POC1A plays a crucial role in the process of EMT, regulating the invasion and metastasis of TNBC in vitro and in vivo. Our RNA sequence results, followed by further investigation, revealed that POC1A promotes the metastasis of TNBC by inducing EMT through the STAT3 signaling pathway.</p><p><strong>Conclusions: </strong>In short, for the first time, we have identified that POC1A plays a pivotal role in regulating the EMT of TNBC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"280"},"PeriodicalIF":6.4,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883203","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":"Targeting LINC02544/miR-497-5p/CAPRIN1 axis via exosome-based siRNA to overcome immunotherapy resistance in triple-negative breast cancer.","authors":"Bin Lian, Jiayi Li, Shihui Tang, Ting Li, Jinping Li","doi":"10.1186/s10020-025-01336-w","DOIUrl":"10.1186/s10020-025-01336-w","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"278"},"PeriodicalIF":6.4,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862339","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":"Role of astrocytes in the pathogenesis of perinatal brain injury.","authors":"Ling Li, Xuewei Cui, Baoli Zhu, Lele Zhou, Yaya Guo, Tianjing Liu, Yongyan Shi","doi":"10.1186/s10020-025-01328-w","DOIUrl":"10.1186/s10020-025-01328-w","url":null,"abstract":"<p><p>Astrocytes, the most abundant glial cells in the central nervous system (CNS), play critical roles in blood-brain barrier (BBB) maintenance, synaptogenesis, neurotransmission, and metabolic regulation. In response to perinatal brain injury, astrocytes release inflammatory mediators that drive neuroinflammation, disrupting normal brain development. Key signaling pathways, including Janus kinase/signal transducers and activators of transcription (JAK/STAT), nuclear factor kappa B (NF-κB), Notch, and glutamate transporter signaling, are activated during this process, contributing to astrocyte dysfunction and neuronal damage. Astrocytes also engage in dynamic crosstalk with microglia, oligodendrocytes, and neurons, further influencing the injury response. Biomarkers such as glial fibrillary acidic protein (GFAP) and calcium-binding protein (S100β) highlight astrocyte activation and its role in pathology. By targeting these signaling pathways and glial interactions, novel therapeutic strategies can be developed to mitigate neurodevelopmental and perinatal brain injuries associated with astrocyte dysfunction.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"277"},"PeriodicalIF":6.4,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12345021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144847587","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":"Nerve growth factor: what can surgeons and oncologists learn from a neurological and psychological biomarker?","authors":"Fei Xiong, Ben-Li Xiao, Qi Wang, Kun Liu, Hong-Wei Wu, Chao Jing, Kui-Nan Tong, Zhong-Tao Zhang, Wei Guo","doi":"10.1186/s10020-025-01333-z","DOIUrl":"10.1186/s10020-025-01333-z","url":null,"abstract":"<p><strong>Background: </strong>As the first discovered member of the neurotrophin family, nerve growth factor (NGF) plays fundamental roles in peripheral sensory and sympathetic neuronal development and survival. Recent evidence reveals its tumour-promoting effects through increasing perineural invasion, which is correlated with poor clinical outcomes. The exact molecular mechanisms exhibit malignancy-specific differences and remain incompletely characterized.</p><p><strong>Main text: </strong>This review compares mechanistic insights and therapeutic advancements regarding NGF signalling in neurological/psychological disorders with discoveries in oncological contexts. Functioning as a dual biomarker for neural integrity and pathological progression, NGF primarily exerts its effects via an interaction with the high-affinity tyrosine kinase receptor. Both molecules are frequently overexpressed in malignant tissues. NGF orchestrates tissue regeneration and tumourigenesis through the activation of conserved neurotrophin pathways and downstream proliferative cascades, some of which participate in regulating the expression and secretion of NGF in turn. In practical applications, in addition to acting as an antiproliferative target, NGF could be utilized in psychological management, antinociceptive treatment, and wound healing.</p><p><strong>Conclusions: </strong>Systemic NGF-targeted therapies have significant articular and neurological toxicity, indicating the critical need for localized intervention strategies depending on the expression level of NGF and TrkA to balance antitumour efficacy with protective requirements for nerve structures and innervation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"276"},"PeriodicalIF":6.4,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812135","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":"Isoimperatorin, a natural furanocoumarin, ameliorates ulcerative colitis by inducing Treg cell generation and promoting mucosal healing.","authors":"Yulai Fang, Shichen Min, Hongxin Chen, Zhenxing Zhu, Yanan Li, Yiheng Tong, Jingyi Hu, Lei Zhu, Hong Shen","doi":"10.1186/s10020-025-01334-y","DOIUrl":"10.1186/s10020-025-01334-y","url":null,"abstract":"<p><strong>Background: </strong>Ulcerative colitis (UC), an autoimmune disorder characterized by chronic intestinal inflammation, primarily targets the colonic mucosa. Isoimperatorin is a natural furanocoumarin compound with a variety of pharmacological activities. However, its therapeutic potential and underlying mechanisms in UC pathogenesis remain to be elucidated.</p><p><strong>Methods: </strong>Mice were administered 2.5% dextran sulfate sodium (DSS) ad libitum to construct a colitis model, and isoimperatorin was given by gavage to evaluate its efficacy. Flow cytometry and qPCR were employed to assess the effect of isoimperatorin on Treg cell generation. Tissue immunofluorescence and Western blot were used to investigate the effects of isoimperatorin on the repair of damaged intestinal barrier. Cell scratching and migration were used to examine the effects of isoimperatorin on wound healing and cell migration. Finally, a Treg cell depletion assay was implemented to verify the Treg cell-dependent effect of isoimperatorin on repairing intestinal barrier injury to ameliorate UC.</p><p><strong>Results: </strong>Oral gavage administration of isoimperatorin (20, 40 mg/kg) significantly improved disease symptoms in UC mice. Isoimperatorin treatment elevated the percentage of Treg cells but had no significant effect on the proportion of Th17 cells in mesenteric lymph node tissues. Isoimperatorin upregulated the expression levels of factors related to mucosal healing and upregulated the expression levels of proteins related to the integrity of the intestinal epithelial barrier. Additionally, isoimperatorin (1, 3 µM) accelerated the migration of colon epithelial cells to facilitate wound healing and also induced the generation of Treg cells in vitro. Finally, Treg cell depletion markedly attenuated isoimperatorin's therapeutic efficacy in intestinal barrier repair and UC amelioration, indicating a Treg cell-dependent mechanism of action.</p><p><strong>Conclusions: </strong>Isoimperatorin promotes intestinal mucosal healing and thus improves UC disease symptoms by inducing Treg cell generation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"275"},"PeriodicalIF":6.4,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799676","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 downregulation of hormone-sensitive lipase and dysregulation of cholesterol receptors/transporter affect testicular lipid homeostasis and function in HFD-induced oligoasthenospermia mice.","authors":"Min Pan, Jingya Li, Yujia Wang, Ziao Liu, Li Li, Tongsheng Wang","doi":"10.1186/s10020-025-01327-x","DOIUrl":"10.1186/s10020-025-01327-x","url":null,"abstract":"<p><strong>Background: </strong>Obesity-induced oligoasthenospermia is associated with testicular lipid metabolism. However, the mechanisms underlying the lipid homeostasis imbalance of obesity-induced oligoasthenospermia are unclear.</p><p><strong>Methods: </strong>Male C57BL/6 mice fed a high-fat diet were established for the in vivo model. TM3/TM4 cells were treated with palmitic acid (PA) in vitro. Proteomics analyzed differential proteins in the testis. The Oil red O and Nile red were used to observe lipid droplets (LDs). Filipin staining was used to observe free cholesterol (FC). Hormone-sensitive lipase (HSL), Low-density lipoprotein receptor (LDLr), Scavenger receptor class B type I (SR-BI), and ATP-binding cassette transporter A1 (ABCA1) expressions were analyzed using qRT-PCR, WB, Immunofluorescence, and immunohistochemistry. Testosterone synthesis and Blood-testis barrier (BTB) integrity were evaluated by ELISA, Transmission electron microscope, and WB.</p><p><strong>Results: </strong>HFD mice exhibited elevated blood lipid, reduced sperm quality, and hormonal imbalances. Meanwhile, testosterone synthesis was impaired, and BTB was damaged in HFD mice. In vivo and in vitro models, LDs deposition was observed, and HSL expression was down-regulated in Leydig and Sertoli cells. However, the expressions of cholesterol uptake receptors and efflux transporters, as well as the levels of FC, in the two cells were inconsistent. In Leydig cells, the expression of cholesterol uptake receptors (LDLr and SR-BI) was upregulated, resulting in increased FC levels. In Sertoli cells, cholesterol efflux transporter (ABCA1) expression was upregulated, and FC levels decreased. Overexpression of HSL ameliorated LDs accumulation and increased testosterone levels.</p><p><strong>Conclusion: </strong>The down-regulation of HSL and dysregulation of cholesterol receptors/transporter may affect lipid homeostasis, thereby damaging testicular function.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"274"},"PeriodicalIF":6.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784858","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 candidate \"kill or cure\" strategies to treat MFN2-related lipodystrophy.","authors":"Ineke Luijten, Xiong Weng, Ula Kibildyte, Jana Buchan, Ami Onishi, Jake Mann, Eleanor McKay, David Savage, Robert K Semple","doi":"10.1186/s10020-025-01314-2","DOIUrl":"10.1186/s10020-025-01314-2","url":null,"abstract":"<p><strong>Background: </strong>The mitofusin 2 (MFN2) R707W mutation causes debilitating human lipodystrophy featuring lower body adipose loss, upper body adipose hyperplasia, and dyslipidaemic insulin resistance. Mechanical complications include airway compromise due to head and neck adipose overgrowth. This condition, sometimes called Multiple Symmetrical Lipomatosis (MSL), is also seen in sporadic form strongly associated with excess ethanol consumption. Mitigating the cellular pathology, or, conversely, exacerbating it, inducing selective death of affected adipocytes, are potential therapeutic strategies.</p><p><strong>Methods: </strong>Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human MFN2^R707W/R707W fibroblasts, and in Mfn2^R707W/R707W mice and derived preadipocytes. Cell survival, mitochondrial network morphology and integrated stress response markers were assessed in cells, and body composition and metabolic indices in mice.</p><p><strong>Results: </strong>Forcing galactose metabolism in human MFN2^R707W/R707W dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2^R707W/R707W white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2^R707W/R707W brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2^R707W/R707W mice, and serum lactate in males. Rapamycin - a candidate mitigating treatment - increased size and mitolysosome content of WT preadipocytes, and to a lesser degree of Mfn2^R707W/R707W preadipocytes. In male Mfn2^R707W/R707W mice, rapamycin reduced weight gain, brown adipose mass, and increased serum Fgf21. Finally, a panel of mitochondrial stressors solicited no selective death or ISR in Mfn2^R707W/R707W preadipocytes.</p><p><strong>Conclusions: </strong>Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"273"},"PeriodicalIF":6.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784857","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":"Piezo1 induces mitochondrial autophagy dysfunction leading to cartilage injury in knee osteoarthritis.","authors":"Likai Yu, Zishan Su, Di Tian, Shangqi Liu, Li Zhang, Zeen Wang, Shaobo Guo, Wenhui Zhu, Peimin Wang, Nongshan Zhang","doi":"10.1186/s10020-025-01335-x","DOIUrl":"10.1186/s10020-025-01335-x","url":null,"abstract":"<p><strong>Background: </strong>External mechanical stress plays a pivotal role in the pathogenesis of knee osteoarthritis. Piezo1 can sense mechanical stress changes on the surface of various cell types and convert them into bioelectrical signals to regulate cellular functions. Therefore, our study aimed to investigate the role of Piezo1 in mechanically induced KOA and elucidate its underlying mechanisms.</p><p><strong>Methods: </strong>In this study, we employed various techniques to assess the effects of mechanical stress on knee joint cartilage in vivo and in vitro experiments. In vivo, we performed Micro-CT scanning, H&E staining, and ELISA analysis on the knee joints to evaluate the degree of cartilage damage and the expression of pro-inflammatory factors. In vitro, we utilized a cell stretcher to apply mechanical stress specifically to chondrocytes. Subsequently, we investigated the expression levels of Piezo1, pro-inflammatory factors, Collagen II, and other relevant markers within the chondrocytes. This approach aimed to shed light on the potential impact of Piezo1 on chondrocytes when subjected to mechanical stress.</p><p><strong>Results: </strong>Elevated expression of Piezo1 was observed in the cartilage of mice post-treadmill exercise intervention, with noticeable damage to the cartilage tissue and reduced surface smoothness. External mechanical stress significantly lowered the synthesis of the extracellular matrix in chondrocytes, potentially through the inhibition of mitochondrial autophagy levels, leading to increased mitochondrial dysfunction and the induction of pro-apoptotic proteins and pro-inflammatory cytokines.</p><p><strong>Conclusions: </strong>Mechanical stress induces extracellular matrix degradation and promotes KOA progression through Piezo1-mediated chondrocyte autophagy dysfunction and apoptotic injury.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"272"},"PeriodicalIF":6.4,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768748","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":"Coniferaldehyde reverses 3-nitropropionic acid-induced Huntington's disease pathologies via PKM2 restoration and JAK2/STAT3 inhibition.","authors":"Ayooluwa Gabriel Ibiayo, Peeraporn Varinthra, Mukundan Nagarajan, Ingrid Y Liu","doi":"10.1186/s10020-025-01308-0","DOIUrl":"10.1186/s10020-025-01308-0","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor decline and neuronal loss, with no curative disease-modifying therapies available. The mitochondrial toxin 3-nitropropionic acid (3-NP) is widely used to model HD-like pathologies. We investigated the therapeutic potential of coniferaldehyde (CFA), a natural phenolic compound with anti-inflammatory, antioxidant, and anti-radical properties, against 3-NP-induced neurodegeneration. Given the roles of oxidative stress, metabolic dysfunction, and neuroinflammation in HD, we hypothesize that CFA exerts neuroprotection by attenuating these processes via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway - a novel target for CFA in HD.</p><p><strong>Methods: </strong>Neurological and behavioral deficits were assessed via neurological assessment scaling, rotarod, and open field tests. Nissl staining was performed to evaluate neuronal damage in the motor cortex and striatum. Dihydroethidium staining (DHE) was used to measure reactive oxygen species (ROS) levels, and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was conducted to detect apoptosis. Western blot assay and immunofluorescence staining were used to examine CFA's effect. Additionally, molecular docking was performed to analyze CFA's interaction with STAT3.</p><p><strong>Results: </strong>CFA treatment significantly improved motor function, preserved neuronal architecture, and reduced apoptosis, as confirmed by Nissl and TUNEL staining. CFA also decreased ROS levels and restored pyruvate kinase M2 (PKM2) expression, a key regulator of metabolic homeostasis. Consistently, CFA attenuated neuroinflammation by suppressing Glial Fibrillary Acidic Protein (GFAP) expression and proinflammatory cytokines Interleukin-6 (IL-6) and Interleukin-1 beta (IL-1β). Molecular docking studies revealed a strong binding affinity between CFA and STAT3, and western blot analysis showed reduced phosphorylation of STAT3, indicating modulation of the JAK2/STAT3 signaling pathway.</p><p><strong>Conclusion: </strong>These findings demonstrate that CFA modulates oxidative, PKM2-mediated metabolic, and inflammatory pathways through the JAK2/STAT3 axis, enhancing motor function and neuronal survival in a 3-NP model of HD. This multi-targeted mechanism highlights its potential as a disease-modifying therapy for advancing therapeutic strategies in HD and related neurodegenerative disorders.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"271"},"PeriodicalIF":6.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753857","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}