Cell Biology and Toxicology最新文献

{"title":"Inhibition of YTHDF2-mediated CYLD mRNA degradation promotes neuronal ferroptosis and pain in Parkinson's disease through NOX4 deubiquitination.","authors":"Fei Wang, Shuwei Bai, Yuanmei Pan, Zhongjiao Lu, Xianguo Jiang","doi":"10.1007/s10565-026-10204-0","DOIUrl":"10.1007/s10565-026-10204-0","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is featured by progressive neurodegeneration linked to iron-dependent ferroptosis, yet the functions of m⁶A RNA-binding proteins and deubiquitinating enzymes in this process remain poorly understood. This work investigates the functional interplay between the m⁶A reader YTHDF2 and deubiquitinase CYLD in PD-associated ferroptosis and delineates their downstream molecular mechanisms.</p><p><strong>Methods: </strong>PD models were established using MPTP-treated C57BL/6 mice and MPP⁺-exposed SH-SY5Y neuroblastoma cells. Behavioral assessments (open field, rotarod, and pole tests) and pain sensitivity assays (mechanical allodynia, thermal hyperalgesia) were performed. Molecular analyses included qRT-PCR, Western blot, RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), and ubiquitination assays. Ferroptosis markers (Fe²⁺, ROS, MDA, and GSH) and key regulators (ACSL4, GPX4, SLC7A11, and FTL) were quantified. Gain- and loss-of-function experiments for YTHDF2, CYLD, and NOX4 were conducted to validate regulatory relationships.</p><p><strong>Results: </strong>MPTP/MPP⁺ treatment downregulated YTHDF2 and upregulated CYLD, exacerbating ferroptosis, as evidenced by mitochondrial damage, elevated Fe²⁺/ROS/MDA, reduced GSH, and altered level of ferroptosis-associated proteins (ACSL4 increased, GPX4/SLC7A11/FTL decreased). YTHDF2 overexpression suppressed ferroptosis, at least in part, by recognizing m6A-modified CYLD mRNA and promoting its degradation. Moreover, CYLD stabilized NOX4 by inhibiting its ubiquitination. Rescue experiments confirmed that CYLD depletion attenuated ferroptosis, an effect that was rescued by NOX4 overexpression. In MPTP-induced mice, YTHDF2 overexpression alleviated motor deficits (improved locomotion, rotarod performance), and reduced pain hypersensitivity, while mitigating ferroptosis markers and nigral mitochondrial pathology.</p><p><strong>Conclusion: </strong>Our study uncovered the YTHDF2/CYLD/NOX4 axis as a novel ferroptosis regulator in PD, revealing a dual epitranscriptomic-posttranslational therapeutic target for neuroprotection.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175592","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":"Circular RNA circTrpc6-induced tau phosphorylation contributes to neuronal injury and cognitive decline via miR-485-5p/eIF4E axis in senescence-accelerated mouse prone 8 mice.","authors":"Jin-Lan Huang, Qiu-Qing Yan, Yan-Bin Guo, Yu-Xuan Du, Ling-Ling Liu, Xiao-Jing Sun, Chao Yu, Deng-Pan Wu","doi":"10.1007/s10565-026-10214-y","DOIUrl":"10.1007/s10565-026-10214-y","url":null,"abstract":"<p><p>Tau hyperphosphorylation, a key neuropathological feature in neurodegenerative disorders, is strongly linked to cognitive decline. CircRNAs are recognized to play a crucial regulatory role in numerous human diseases, yet their impacts on neurodegenerative diseases remain unclear. This study was aimed to characterize and analyze the contribution of circTrpc6 to neurodegeneration and its molecular mechanisms. We found that circTrpc6 was mainly expressed in the hippocampal and cortical regions and was a cytoplastic circRNA with high abundance in neuronal cells, and its expression was upregulated in the SAMP8 hippocampus. CircTrpc6 knockdown attenuated tau phosphorylation and aggregation in N2a cells and the SAMP8 hippocampus, alleviated hippocampal neuronal and synaptic injury and improved cognitive function of SAMP8 mice. Overexpression of circTrpc6 increased tau phosphorylation and aggregation in N2a cells. Mechanistically, circTrpc6 could modulate eIF4E and p-eIF4E expression and the interaction of eIF4E and tau mRNA via interacting with miR-485-5p and influencing miR-485-5p expression, thus regulating tau phosphorylation and aggregation and affecting cognitive function. Collectively, our work indicates a crucial role of circTrpc6 in regulating tau phosphorylation and cognitive function via miR-485-5p/eIF4E axis, and implies that circTrpc6 may serve as an important regulator in tau phosphorylation and represents a potential target for treatment of cognitive decline in neurodegenerative diseases.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13447473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148581","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":"EZH2/DUSP1/Akt signaling axis mediates the inhibitory effect of crebanine on hepatocellular carcinoma progression.","authors":"Jinxia Qi, Zhikai Wen, Yanju Ren, Gang Huang, Yuan Wang, Qingqing Ruan, Chunmei Wen, Jiale Xu, Mengyao Wang, Xingyue Wang, Hanbin Chen, Yihu Zheng, Jie Deng","doi":"10.1007/s10565-026-10216-w","DOIUrl":"10.1007/s10565-026-10216-w","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is characterized by a subtle onset, rapid development, and high malignancy. Traditional treatments have struggled to cure patients with advanced HCC. Crebanine is an isoquinoline aporphine alkaloid extracted from Stephania venosa. Few studies have focused on the therapeutic potential and molecular mechanisms of crebanine in HCC. Herein, to comprehensively evaluate the anti-HCC effect of crebanine in HCC and to further investigate the underlying mechanisms, potential therapeutic role of crebanine against HCC malignancy was assessed through in vitro and in vivo experiments. We carried out a panel of experiments covering cell viability, colony formation, apoptosis detection, migration, invasion and western blot analysis. Results revealed that crebanine suppresses proliferation, migration and invasion, and triggers apoptosis in HepG2 and Huh7 cells. Mechanistically, crebanine treatment increased DUSP1 expression while decreasing EZH2 and p-Akt expressions. Crebanine promoted DUSP1 transcription through repressing EZH2 expression, thereby inhibiting Akt phosphorylation. Knockdown of DUSP1 diminished the anti-HCC effects of crebanine while activating Akt signaling. Overexpression of EZH2 abolished crebanine-induced DUSP1 upregulation and the cytostatic effects in HCC both in vitro and vivo. Overall, crebanine effectively suppresses HCC tumor growth and progression via modulation of the EZH2/DUSP1/Akt signaling pathway. Crebanine shows potential as a promising therapeutic agent for HCC treatment.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142834","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":"Integrative multi-omics, machine learning, and experimental validation reveal that TPM1 suppresses M2 macrophage polarization and enhances chemosensitivity in acute myeloid leukemia.","authors":"Yue Li, Baosheng Wei, Liuping Hu, Yuzhen Du","doi":"10.1007/s10565-026-10201-3","DOIUrl":"10.1007/s10565-026-10201-3","url":null,"abstract":"<p><strong>Background: </strong>Acute myeloid leukemia (AML) remains a therapeutic challenge due to chemoresistance and immunosuppression. This study aimed to discover novel regulatory mechanisms in AML pathogenesis.</p><p><strong>Methods: </strong>Integrative transcriptomic (GSE30029) and proteomic (PXD008378) analyses with machine learning (LASSO, SVM-RFE, random forest) were performed to identify core AML regulators. Functional validation was conducted in AML cell lines (HL-60, NB4), including cell proliferation and apoptosis assays, cytarabine (Ara-C) sensitivity testing, and a subcutaneous xenograft model. Macrophage polarization was evaluated in co-culture systems. Molecular mechanisms were explored via MeRIP, RIP, and mRNA stability assays.</p><p><strong>Results: </strong>Tropomyosin 1 (TPM1) was identified as a potential key factor in AML. TPM1 was downregulated in AML tissues and cells. TPM1 overexpression inhibited AML cell proliferation, promoted apoptosis and oxidative stress, and enhanced sensitivity to Ara-C. Furthermore, TPM1 upregulation attenuated M2 macrophage polarization. Mechanistically, the m6A eraser fat mass and obesity-associated protein (FTO) destabilized TPM1 mRNA in an m6A-dependent manner. Downregulation of TPM1 reversed the effects of FTO depletion on AML cell proliferation, Ara-C sensitivity, and M2 macrophage polarization.</p><p><strong>Conclusion: </strong>This study unveils a novel FTO/m6A/TPM1 axis that coordinately governs AML cell growth, chemosensitivity, and macrophage polarization, highlighting it as a promising therapeutic target.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052952","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":"Integrated lipidome and miRNome analyses reveal sex-based differences in circulating extracellular vesicles of alcohol use disorder patients.","authors":"Carla Perpiñá-Clérigues, Susana Mellado, Cristina Galiana-Roselló, Saritha Kodikara, Blanca Martín-Urdiales, Miguel Marcos, Kim-Anh Lê Cao, Francisco García-García, María Pascual","doi":"10.1007/s10565-026-10213-z","DOIUrl":"10.1007/s10565-026-10213-z","url":null,"abstract":"<p><p>Integrated multi-omics and extracellular vesicle (EV) analysis are emerging as powerful, complementary strategies for biomarker discovery. These approaches offer promising tools to enhance early detection, diagnosis, and treatment of alcohol use disorder (AUD). Here we applied an integrated miRNomic and lipidomic approach to analyze plasma EVs from AUD patients and controls of both sexes to gain a comprehensive understanding of the underlying molecular mechanisms. We identified an AUD signature with predictive potential for diagnostic applications, representing an initial step in this direction. Individual features (e.g., hsa-miR-99b-3p, hsa-miR-556-5p, Cer_NDS-d39:1, and PI18:0_18:2) represented important components; however, the strength of this signature lay in the combined profile rather than isolated markers. We also revealed an AUD-sex signature that provided insight into how biological responses to alcohol differ between females and males (including features such as hsa-miR-1301-3p and PC39:4), which also underscored the power of multi-omic integration. The individual miRNome approach also revealed an opposite functional alteration by sex in various alcohol related systems, such as pathways associated with immunity, oxidative stress, and autophagy. An open-access Shiny web application ( https://carpercle.shinyapps.io/SexEVEthOmics/ ) accompanies this study, providing interactive access to the complete dataset and additional analyses for customized exploration. Together, our findings underscore the added value of multi-omics integration in identifying disease-associated molecular signatures. This sex-informed approach highlights a promising avenue for the development of more personalized diagnostic tools and therapeutic strategies in AUD.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013946","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":"Decoding shared pathogenic networks of oxidative stress in neuropsychiatric disorders to prioritize multi-target therapeutics from natural products.","authors":"Xuan Xu, Zhu Ni, Yan-Bin Wang, Sha-Sha Fan, Yanan Du, Xu Wang, Xiang-Yu Meng","doi":"10.1007/s10565-026-10208-w","DOIUrl":"10.1007/s10565-026-10208-w","url":null,"abstract":"<p><strong>Background: </strong>Neurodegenerative and psychiatric disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia (SZ), are characterized by progressive neuronal loss and synaptic dysfunction. Despite their severity, effective disease-modifying treatments remain unavailable, largely due to the elusive nature of their underlying molecular mechanisms.</p><p><strong>Methods: </strong>To elucidate these mechanisms, we conducted an integrative systems biology analysis incorporating transcriptomic datasets, in silico proteomic networks, and inferred metabolomic profiles. Machine learning (ML) and deep learning (DL) models were employed to identify regulatory networks associated with oxidative stress, immune response, and synaptic signaling. Furthermore, network pharmacology approaches were applied to explore multi-target intervention strategies using bioactive compounds from traditional Chinese medicine (TCM).</p><p><strong>Results: </strong>Our integrative analysis revealed extensive overlap in dysregulated biological processes across all four disorders, particularly involving oxidative stress and immune activation. We identified TP53, NFE2L2, and PPP3CA as central regulatory hubs driving these pathologies. Notably, computational predictions highlighted that TCM-derived compounds, specifically stigmasterol and dodecanoic acid, exhibit promising multi-target effects for modulating these oxidative and inflammatory responses. Subsequent in vivo experimental validation was performed exclusively to corroborate the disease-associated pathways and core gene dysregulation in an Aβ₄₂-induced AD model. These findings demonstrated molecular and behavioral phenotypes consistent with our multi-dimensional computational predictions, establishing a robust mechanistic rationale that merits future in vivo pharmacological validation for the predicted bioactive compounds.</p><p><strong>Conclusion: </strong>This study highlights the utility of a multi-disease, multi-dimensional framework in uncovering shared pathogenic signatures. By integrating computational analytics with pharmacological modeling and experimental validation, we identified key regulatory genes and natural compounds with therapeutic potential. These findings provide a theoretical foundation for the development of multi-target, personalized treatment strategies against neurodegeneration.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13369711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980600","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":"SIRT5-mediated HSDL2 desuccinylation promotes diabetic-associated cognitive dysfunction via disrupting mitochondrial TRAP1.","authors":"Yinmeng Qu, Renjie Liu, Xuan Chen, Peifan Wu, Yuhao Zhao","doi":"10.1007/s10565-026-10210-2","DOIUrl":"10.1007/s10565-026-10210-2","url":null,"abstract":"<p><p>Diabetic-associated cognitive dysfunction (DACD) is a severe complication of diabetes characterized by mitochondrial failure in hippocampal neurons, yet its precise molecular drivers remain poorly understood. Here, hydroxysteroid dehydrogenase-like 2 (HSDL2) was identified as a key mitochondrial-related protein significantly upregulated in DACD models. Knockdown of HSDL2 alleviated cognitive impairment, synaptic loss, and neuronal apoptosis in DACD mice. Mechanistic investigations revealed that HSDL2 promoted mitochondrial dysfunction and neuronal apoptosis by downregulating TNF receptor-associated protein 1 (TRAP1). Furthermore, HSDL2 was identified as a novel substrate of the desuccinylase sirtuin 5 (SIRT5). SIRT5 mediated HSDL2 desuccinylation at the K42 site to stabilize its protein, leading to its upregulation. Importantly, SIRT5 was upregulated in DACD, and its knockdown mitigated hippocampal damage and cognitive dysfunction. This study unveiled a novel SIRT5/HSDL2/TRAP1 axis in DACD pathogenesis, wherein SIRT5 upregulation drove HSDL2 desuccinylation and stabilization, ultimately promoting mitochondrial dysfunction and cognitive decline via downregulation of TRAP1.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13369707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980662","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":"ARF6 promotes the nuclear translocation of β-catenin to facilitate AFP deficiency-mediated metastasis in CTNNB1^S33Y-mutant hepatocellular carcinoma.","authors":"Ruitian Zhang, Longxuan Dong, Junyi Yang, Qinglong Guo, Di Pan, Chen Xun, Libin Wei","doi":"10.1007/s10565-026-10211-1","DOIUrl":"10.1007/s10565-026-10211-1","url":null,"abstract":"<p><p>The mortality rate associated with hepatocellular carcinoma (HCC) remains alarmingly high, positioning it as a primary lethal cancer worldwide, primarily driven by its high degree of malignancy, recurrence, and metastasis. The high heterogeneity of HCC necessitates the urgent identification of new therapeutic targets and molecular pathways. Our previous research observed that alpha-fetoprotein (AFP) deficiency led to pro-metastatic roles in HCC with specific genotypes. Here, we further investigated the underlying molecular mechanism. Through proteome microarray screening, we identified that ADP-ribosylation factor 6 (ARF6) was a key AFP-interacting protein and AFP deficiency upregulated ARF6 activity, which subsequently promoted the metastatic capacity of HepG2 cells. Mechanistically, the abnormal activation of ARF6 induced the dissociation of β-catenin from its membrane-bound anchors, specifically E-cadherin. The consequent increase in free cytoplasmic β-catenin facilitates its nuclear translocation, which in turn activates Wnt/β-catenin pathway. Crucially, we discovered that the pro-metastatic function of activated ARF6 and the sensitivity to the ARF6 inhibitor were strictly dependent on the CTNNB1 genotype. In highly invasive MHCC-97H cells, which harbor a CTNNB1 nonsense mutation, ARF6 inhibitor SecinH3 failed to inhibit migration and invasion. However, the overexpression of CTNNB1^S33Y mutation in MHCC-97H cells further amplified the increasing transcriptional activity of β-catenin triggered by the ARF6 abnormal activation. Importantly, the reintroducion of CTNNB1^S33Y mutation restored the inhibitory effect of SecinH3 in vitro and significantly suppressed the hepatic and pulmonary metastasis in a tail vein injection HCC metastasis mouse model. These findings establish a CTNNB1^S33Y-dependent mechanism for ARF6-mediated metastasis, indicating that CTNNB1 activating mutations serve as a \"permissive signal\" for ARF6's pro-metastatic program. Our study underscores the importance of CTNNB1 genotype screening for precisely stratifying patients for ARF6-targeted therapies, offering new medication guidance for highly heterogeneous HCC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980614","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":"ALKBH5-mediated m6A demethylation of PRMT6 inhibits neuronal apoptosis and ferroptosis in Alzheimer's disease via reducing transcription of ACSL4.","authors":"Jingwei Cao, Haining Wang, Baichao Han, Jihe Song, Zhanbin Tang","doi":"10.1007/s10565-026-10197-w","DOIUrl":"10.1007/s10565-026-10197-w","url":null,"abstract":"<p><strong>Background: </strong>Protein arginine methyltransferase 6 (PRMT6) is confirmed to regulate Alzheimer's disease (AD) process. Acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis is involved in regulating AD progression. However, whether PRMT6 regulates AD progression through ACSL4-mediated ferroptosis is unknown.</p><p><strong>Methods: </strong>AD mice were injected with adeno-associated virus to explore the role of PRMT6 and AlkB homologue 5 (ALKBH5) in vivo. Neuronal cells were treated with amyloid-β protein fragment 1-42 (Aβ1-42) to mimic AD cell models. The expression levels of PRMT6, ALKBH5, ACSL4, GPX4, and SLC7A11 were tested by qRT-PCR or western blot. Cell viability and apoptosis were detected by CCK8 assay and TUNEL staining. The levels of ROS, MDA, SOD and Fe²⁺ were tested to evaluate ferroptosis. Mouse behavior, neuron injury, Aβ deposition, and neuronal cell apoptosis were examined by morris water maze test, novel object recognition test, histological staining and TUNEL staining. The interactions between PRMT6 and ALKBH5 or ACSL4 were analyzed.</p><p><strong>Results: </strong>PRMT6 expression was upregulated in AD mice. Silencing of PRMT6 repressed Aβ1-42-induced neuronal cell apoptosis and ferroptosis, as well as alleviated cognitive deficits in AD mice. ALKBH5 reduced PRMT6 expression by inhibiting its m6A modification. ALKBH5 overexpression suppressed Aβ1-42 induced apoptosis and ferroptosis in neuronal cells, and this effect was reversed by PRMT6 upregulation. Besides, PRMT6 promoted ACSL4 expression via increasing H3R2me2a on the ACSL4 promoter, and ACSL4 overexpression also abolished the inhibitory effect of PRMT6 knockdown on Aβ1-42-induced cell ferroptosis. Meanwhile, ALKBH5 inhibited neuronal cell ferroptosis to relieve cognitive deficits in AD mice via repressing the PRMT6/ACSL4 axis.</p><p><strong>Conclusion: </strong>ALKBH5 could inhibit neuronal cell ferroptosis to alleviate the progression of AD by decreasing PRMT6-mediated ACSL4 transcription through H3R2me2a.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13369058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980587","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":"Mechanisms of TRIM21-mediated RUNX2 degradation via chaperone-mediated autophagy in periodontitis.","authors":"Yi Zhao, Yuyu Ge, Qiaoli Zhai, Zhiqiang Wang","doi":"10.1007/s10565-026-10209-9","DOIUrl":"10.1007/s10565-026-10209-9","url":null,"abstract":"<p><p>The osteogenic capability of periodontal ligament cells in periodontitis is impaired partly due to decreased RUNX2 expression. Mass spectrometry identified TRIM21 as a protein that interacts with RUNX2 and facilitates its degradation. Pharmacological inhibition experiments revealed that blocking the lysosomal pathway significantly attenuated TRIM21-mediated RUNX2 degradation, whereas inhibition of the proteasome or macroautophagy had no such effect. Subsequent analysis revealed that the KFERQ-like motif in TRIM21 is crucial for its identification in chaperone-mediated autophagy (CMA). TRIM21 mutants lacking this motif failed to bind the chaperone protein HSC70 and could not mediate RUNX2 degradation. HSC70 identifies the KFERQ motif in TRIM21, aiding the transport of the TRIM21-RUNX2 complex to lysosomal-associated membrane protein 2A (LAMP2A) on the lysosome surface, which promotes RUNX2 degradation. In conclusion, our study demonstrated that TRIM21 mediated RUNX2 degradation through the lysosome-mediated CMA, driven by its interaction with HSC70 via the KFERQ motif. This mechanism is exacerbated in periodontitis due to elevated TRIM21 expression, leading to reduced RUNX2 levels. These findings provide new insights into the impaired osteogenic capacity in periodontitis and highlight TRIM21 as a potential therapeutic target to restore RUNX2 function and enhance bone regeneration in periodontal disease.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13369236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980690","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}