Pub Date : 2026-03-01Epub Date: 2025-12-13DOI: 10.1016/j.bbadis.2025.168132
Liman Lin , Chunle Zhao , Xiaoya Cai , Aiguo Liu , Min Xiao , Liting Chen , Dengju Li
Chemotherapy resistance represents a major challenge in relapsed and refractory acute myeloid leukemia (AML). Therefore, it is necessary to investigate the mechanisms underlying chemotherapy resistance in AML. INSR not only highly expressed in AML cells treated with chidamide, but also elevated in AML patients. Subsequent overexpression and knockdown experiments of INSR in AML cells demonstrated that INSR facilitates cell cycle transition from G1 to S phase and promotes AML cell proliferation. Furthermore, INSR upregulates vimentin and N-cadherin expression, thereby enhancing cell invasion and migration. By integrating transcriptome sequencing data with gene expression profile interactive analysis, we discovered that AKT1 expression levels were positively correlated with INSR expression, while AKT1 expression exhibited a negative correlation with the prognosis of AML patients. AKT1 expression inhibition reduced the proliferation and migratory activity of AML cells. Additionally, suppressing AKT1 expression diminished the impact of INSR on promoting AML cells proliferation, invasion, and migration. This study indicates that INSR expression is elevated in AML cells after treating with chidamide and that INSR promotes AML cells proliferation and migration by upregulating AKT1 expression.
{"title":"INSR/AKT1 axis promotes cells proliferation and migration in acute myeloid leukemia","authors":"Liman Lin , Chunle Zhao , Xiaoya Cai , Aiguo Liu , Min Xiao , Liting Chen , Dengju Li","doi":"10.1016/j.bbadis.2025.168132","DOIUrl":"10.1016/j.bbadis.2025.168132","url":null,"abstract":"<div><div>Chemotherapy resistance represents a major challenge in relapsed and refractory acute myeloid leukemia (AML). Therefore, it is necessary to investigate the mechanisms underlying chemotherapy resistance in AML. INSR not only highly expressed in AML cells treated with chidamide, but also elevated in AML patients. Subsequent overexpression and knockdown experiments of INSR in AML cells demonstrated that INSR facilitates cell cycle transition from G1 to S phase and promotes AML cell proliferation. Furthermore, INSR upregulates vimentin and N-cadherin expression, thereby enhancing cell invasion and migration. By integrating transcriptome sequencing data with gene expression profile interactive analysis, we discovered that AKT1 expression levels were positively correlated with INSR expression, while AKT1 expression exhibited a negative correlation with the prognosis of AML patients. AKT1 expression inhibition reduced the proliferation and migratory activity of AML cells. Additionally, suppressing AKT1 expression diminished the impact of INSR on promoting AML cells proliferation, invasion, and migration. This study indicates that INSR expression is elevated in AML cells after treating with chidamide and that INSR promotes AML cells proliferation and migration by upregulating AKT1 expression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168132"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-15DOI: 10.1016/j.bbadis.2025.168131
Qianqian Han , Yutong Zou , Qing Yang , Enrong Ran , Ziyao Li , Fang Liu
CD4+ T cells play a critical role in diabetic nephropathy (DN) progression. High-glucose (HG) conditions induce small extracellular vesicle (sEV) cargo loading disorders, but whether CD4+ T cells mediate renal injury via sEVs remains unclear. In vitro, a transformed C3H mouse kidney-1 (TCMK-1)/CD4+ T-cell coculture model revealed that high-glucose (HG) conditions increased CD4+ T-cell-induced lactate dehydrogenase release, reactive oxygen species production, apoptosis of TCMK-1 cells, and mitochondrial dysfunction, as confirmed by enzyme-linked immunosorbent assays, flow cytometry, Western blotting (WB), and transmission electron microscopy (TEM). Notably, compared with those under normal glucose conditions, CD4+ T cells under HG conditions exacerbated these effects more significantly. In vivo, CD4+ T cells were isolated from the blood of C57BL/6J (control) mice and db/db (experimental) mice using magnetic beads, and their sEVs were extracted from the culture medium. These sEVs were injected into corresponding C57BL/6J or db/db mice, with saline-injected mice used as blank controls. Compared with control mice, mice injected with db/db mouse CD4+ T-cell-derived sEVs (both C57BL/6J and db/db recipients) exhibited significant increases in serum creatinine levels and proteinuria, as well as more severe renal pathological injury. TEM, flow cytometry and WB analyses revealed disordered mitochondrial dynamics in renal tubular epithelial cells (RTECs), marked by reduced membrane potential and imbalanced Drp1/Mfn1/Mfn2 expression. Collectively, these findings indicate that CD4+ T cells exacerbate renal injury and disrupt mitochondrial homeostasis in RTECs by releasing sEVs under HG conditions, highlighting the CD4+ T-cell-sEV axis as a potential diagnostic and therapeutic target for DN.
{"title":"CD4+ T-cell-derived small extracellular vesicles induce the apoptosis of renal tubular epithelial cells in diabetic nephropathy by regulating mitochondrial dynamics","authors":"Qianqian Han , Yutong Zou , Qing Yang , Enrong Ran , Ziyao Li , Fang Liu","doi":"10.1016/j.bbadis.2025.168131","DOIUrl":"10.1016/j.bbadis.2025.168131","url":null,"abstract":"<div><div>CD4+ T cells play a critical role in diabetic nephropathy (DN) progression. High-glucose (HG) conditions induce small extracellular vesicle (sEV) cargo loading disorders, but whether CD4+ T cells mediate renal injury via sEVs remains unclear. In vitro, a transformed C3H mouse kidney-1 (TCMK-1)/CD4+ T-cell coculture model revealed that high-glucose (HG) conditions increased CD4+ T-cell-induced lactate dehydrogenase release, reactive oxygen species production, apoptosis of TCMK-1 cells, and mitochondrial dysfunction, as confirmed by enzyme-linked immunosorbent assays, flow cytometry, Western blotting (WB), and transmission electron microscopy (TEM). Notably, compared with those under normal glucose conditions, CD4+ T cells under HG conditions exacerbated these effects more significantly. In vivo, CD4+ T cells were isolated from the blood of C57BL/6J (control) mice and db/db (experimental) mice using magnetic beads, and their sEVs were extracted from the culture medium. These sEVs were injected into corresponding C57BL/6J or db/db mice, with saline-injected mice used as blank controls. Compared with control mice, mice injected with db/db mouse CD4+ T-cell-derived sEVs (both C57BL/6J and db/db recipients) exhibited significant increases in serum creatinine levels and proteinuria, as well as more severe renal pathological injury. TEM, flow cytometry and WB analyses revealed disordered mitochondrial dynamics in renal tubular epithelial cells (RTECs), marked by reduced membrane potential and imbalanced Drp1/Mfn1/Mfn2 expression. Collectively, these findings indicate that CD4+ T cells exacerbate renal injury and disrupt mitochondrial homeostasis in RTECs by releasing sEVs under HG conditions, highlighting the CD4+ T-cell-sEV axis as a potential diagnostic and therapeutic target for DN.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168131"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-24DOI: 10.1016/j.bbadis.2025.168148
Deepak Kunhi Valappil , Priyadarshini Veerabhadraswamy , Prakhyath Hegde , Shruthi Pandey , Shylaja Partha Sarathi , Jeevan M. Gowda , Ravi S. Muddashetty , Anujith Kumar , Nikhil R. Gandasi , Sangeeta Nath
The interaction of amyloid-β (Aβ) peptides with the plasma membrane (PM) is a potential trigger that initiates the formation of higher-order aggregates, membrane alterations/damage, and progressive neurotoxicity in Alzheimer's disease (AD). Recent studies showed neurons initiate PM repair upon damage induced by Aβ aggregates, and dysfunctional repair mechanisms contribute to neurodegeneration. This study uncovers a previously unrecognized molecular coupling between Rab3a-mediated exocytosis and pPAK1-driven endocytosis as a pivotal mechanism of PM repair in neuronal cells and primary neurons exposed to aggregation-prone oligomers of Aβ (oAβ). Unlike earlier reports that broadly associated PM damage and repair with Aβ aggregates, we specifically demonstrate that toxic oAβ1–42, but not oAβ1–40, provokes a highly efficient Rab3a-dependent exocytic repair response, tightly synchronized with pPAK1-mediated endocytosis. Using TIRF microscopy, we dissected the kinetics of vesicle fusion at nanometer-scale resolution and revealed that repair is initiated within minutes of oAβ1–42 exposure, with Rab3a activity dominating the critical first hour of response. Perturbation of this system—via IPA-3–mediated PAK1 inhibition or shRNA knockdown of Rab3a—abolished repair efficiency, establishing a direct causal link between these pathways. Furthermore, the long-term accumulation of oAβ in lysosomes was found to disrupt Rab3a recycling, implicating lipid-microdomain dynamics in the progressive failure of repair machinery in AD model, underscoring their physiological relevance. This study uniquely defines the synchronized action of exocytosis-endocytosis in PM repair via pPAK and Rab3a coordinated machinery as a critical neuronal survival strategy and highlights its specific failure as a mechanistic contributor to AD pathogenesis.
淀粉样蛋白-β (a β)肽与质膜（PM）的相互作用是阿尔茨海默病（AD）中启动高阶聚集体形成、膜改变/损伤和进行性神经毒性的潜在触发因素。最近的研究表明，神经元在Aβ聚集体引起的损伤后启动PM修复，功能失调的修复机制有助于神经退行性变。这项研究揭示了rab3a介导的胞外作用和ppak1驱动的胞吞作用之间的分子耦合，这是暴露于易于聚集的a β低聚物（oAβ）的神经细胞和原代神经元质膜（PM）修复的关键机制。与之前的报道广泛地将PM损伤和修复与a β聚集体联系起来不同，我们特别证明了有毒的oAβ1-42，而不是oAβ1-40，激发了高效的rab3a依赖的胞外修复反应，与ppak1介导的内吞噬紧密同步。使用TIRF显微镜，我们在纳米尺度分辨率下解剖了囊泡融合的动力学，发现修复在暴露于oAβ1-42的几分钟内开始，Rab3a活性主导了反应的关键第一个小时。通过ipa -3介导的PAK1抑制或shRNA敲低rab3a，对这一系统的扰动会破坏修复效率，从而在这些途径之间建立直接的因果关系。此外，研究发现溶酶体中oAβ的长期积累会破坏Rab3a的再循环，这暗示了AD模型中脂质微域动力学与修复机制的渐进式失效有关，强调了它们的生理相关性。本研究独特地定义了胞外-内吞作用在PM修复中的同步作用，通过pPAK和Rab3a协调机制作为关键的神经元生存策略，并强调了其特异性失败作为AD发病机制的机制因素。
{"title":"Repair of amyloid-β–induced plasma membrane damage via coordinated P21-activated kinase activation and Rab3a-directed vesicle fusion","authors":"Deepak Kunhi Valappil , Priyadarshini Veerabhadraswamy , Prakhyath Hegde , Shruthi Pandey , Shylaja Partha Sarathi , Jeevan M. Gowda , Ravi S. Muddashetty , Anujith Kumar , Nikhil R. Gandasi , Sangeeta Nath","doi":"10.1016/j.bbadis.2025.168148","DOIUrl":"10.1016/j.bbadis.2025.168148","url":null,"abstract":"<div><div>The interaction of amyloid-β (Aβ) peptides with the plasma membrane (PM) is a potential trigger that initiates the formation of higher-order aggregates, membrane alterations/damage, and progressive neurotoxicity in Alzheimer's disease (AD). Recent studies showed neurons initiate PM repair upon damage induced by Aβ aggregates, and dysfunctional repair mechanisms contribute to neurodegeneration. This study uncovers a previously unrecognized molecular coupling between Rab3a-mediated exocytosis and pPAK1-driven endocytosis as a pivotal mechanism of PM repair in neuronal cells and primary neurons exposed to aggregation-prone oligomers of Aβ (oAβ). Unlike earlier reports that broadly associated PM damage and repair with Aβ aggregates, we specifically demonstrate that toxic oAβ<sub>1–42</sub>, but not oAβ<sub>1–40</sub>, provokes a highly efficient Rab3a-dependent exocytic repair response, tightly synchronized with pPAK1-mediated endocytosis. Using TIRF microscopy, we dissected the kinetics of vesicle fusion at nanometer-scale resolution and revealed that repair is initiated within minutes of oAβ<sub>1–42</sub> exposure, with Rab3a activity dominating the critical first hour of response. Perturbation of this system—via IPA-3–mediated PAK1 inhibition or shRNA knockdown of Rab3a—abolished repair efficiency, establishing a direct causal link between these pathways. Furthermore, the long-term accumulation of oAβ in lysosomes was found to disrupt Rab3a recycling, implicating lipid-microdomain dynamics in the progressive failure of repair machinery in AD model, underscoring their physiological relevance. This study uniquely defines the synchronized action of exocytosis-endocytosis in PM repair via pPAK and Rab3a coordinated machinery as a critical neuronal survival strategy and highlights its specific failure as a mechanistic contributor to AD pathogenesis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168148"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-10DOI: 10.1016/j.bbadis.2025.168137
Yadi Huang , Yuxin Fan , Yang Liu , Xuan Liu , Wei Li , Ying Yang , Ziyue Zhang , Shifeng Ma , Shuhui Ji , Shanshan Chen , Hua Shu , Wenli Feng , Kunling Wang , Qing He , Wenjun Qi , Ming Liu , Xin Li , Yu Fan
Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young type 2 (GCK-MODY), a monogenic diabetes subtype characterized by stable hyperglycemia and low complication risk. However, the long-term effects of distinct dietary patterns on lipid metabolism and chronic complications in GCK-MODY remain poorly understood. In this study, we employed a knock-in mouse model carrying a novel MODY-associated mutation, GCK-Q26L (hereafter called GCKMut), to systematically investigate age- and diet-dependent changes in lipid homeostasis and microvascular pathology. When fed a normal diet, GCKMut mice developed progressive renal injury by 60 weeks, characterized by NF-κB pathway activation and upregulation of pro-inflammatory and fibrotic mediators. In contrast, GCKMut mice fed a high-fat diet at 28 weeks showed improved lipid profiles and reduced renal injury, accompanied by PPAR-driven fatty acid oxidation. However, these benefits declined by 40 weeks and reversed to dyslipidemia and nephropathy by 60 weeks. Together, these findings demonstrate that GCK inactivation exerts strong age- and diet-dependent effects on renal metabolism and microvascular integrity. The study highlights previously underestimated long-term risks in GCK-MODY and establishes a useful model for mechanistic insight and therapeutic exploration.
{"title":"Duration-dependent alterations of lipid profiles and microvascular complications in GCK-MODY","authors":"Yadi Huang , Yuxin Fan , Yang Liu , Xuan Liu , Wei Li , Ying Yang , Ziyue Zhang , Shifeng Ma , Shuhui Ji , Shanshan Chen , Hua Shu , Wenli Feng , Kunling Wang , Qing He , Wenjun Qi , Ming Liu , Xin Li , Yu Fan","doi":"10.1016/j.bbadis.2025.168137","DOIUrl":"10.1016/j.bbadis.2025.168137","url":null,"abstract":"<div><div>Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young type 2 (GCK-MODY), a monogenic diabetes subtype characterized by stable hyperglycemia and low complication risk. However, the long-term effects of distinct dietary patterns on lipid metabolism and chronic complications in GCK-MODY remain poorly understood. In this study, we employed a knock-in mouse model carrying a novel MODY-associated mutation, GCK-Q26L (hereafter called GCK<sup>Mut</sup>), to systematically investigate age- and diet-dependent changes in lipid homeostasis and microvascular pathology. When fed a normal diet, GCK<sup>Mut</sup> mice developed progressive renal injury by 60 weeks, characterized by NF-κB pathway activation and upregulation of pro-inflammatory and fibrotic mediators. In contrast, GCK<sup>Mut</sup> mice fed a high-fat diet at 28 weeks showed improved lipid profiles and reduced renal injury, accompanied by PPAR-driven fatty acid oxidation. However, these benefits declined by 40 weeks and reversed to dyslipidemia and nephropathy by 60 weeks. Together, these findings demonstrate that GCK inactivation exerts strong age- and diet-dependent effects on renal metabolism and microvascular integrity. The study highlights previously underestimated long-term risks in GCK-MODY and establishes a useful model for mechanistic insight and therapeutic exploration.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168137"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-23DOI: 10.1016/j.bbadis.2025.168146
Yujing Shi , Zhaoyue Zhang , Xiaoke Di , Gefenqiang Shen , Meng Tian , Caiqiang Zhu , Xinchen Sun , Jiahang Song , Hongyan Cheng , Yuanyuan Sun
Cervical cancer (CC) is still a major gynecological tumor among women globally. The heterogeneity landscape and prognostic value of metabolic reprogramming in CC remain unclear. Our research first uncovered metabolic heterogeneity and identified three distinct metabolic subtypes in CC. Based on transcriptomic differences between metabolic subtypes, we developed a robust prognostic signature (TPM3, MAP7, PFKP, IL3RA, ISCU) using machine learning, which robustly stratified patient risk. CC patients with higher risk scores presented unfavorable outcomes and showed an immunosuppressive status. Functional experiments confirmed that phosphofructokinase, platelet (PFKP) promotes CC proliferation and glycolysis. Moreover, we demonstrated that Suramin effectively suppressed CC tumor growth by inhibiting PFKP-mediated glycolysis. Our findings provide a robust prognostic model and disclose PFKP as a potential therapeutic target in CC, offering insightful guidance on cancer management of CC patients.
{"title":"Integrative analysis of single-cell and bulk transcriptomes reveals metabolic heterogeneity and identifies PFKP as a therapeutic target in cervical cancer","authors":"Yujing Shi , Zhaoyue Zhang , Xiaoke Di , Gefenqiang Shen , Meng Tian , Caiqiang Zhu , Xinchen Sun , Jiahang Song , Hongyan Cheng , Yuanyuan Sun","doi":"10.1016/j.bbadis.2025.168146","DOIUrl":"10.1016/j.bbadis.2025.168146","url":null,"abstract":"<div><div>Cervical cancer (CC) is still a major gynecological tumor among women globally. The heterogeneity landscape and prognostic value of metabolic reprogramming in CC remain unclear. Our research first uncovered metabolic heterogeneity and identified three distinct metabolic subtypes in CC. Based on transcriptomic differences between metabolic subtypes, we developed a robust prognostic signature (TPM3, MAP7, PFKP, IL3RA, ISCU) using machine learning, which robustly stratified patient risk. CC patients with higher risk scores presented unfavorable outcomes and showed an immunosuppressive status. Functional experiments confirmed that phosphofructokinase, platelet (PFKP) promotes CC proliferation and glycolysis. Moreover, we demonstrated that Suramin effectively suppressed CC tumor growth by inhibiting PFKP-mediated glycolysis. Our findings provide a robust prognostic model and disclose PFKP as a potential therapeutic target in CC, offering insightful guidance on cancer management of CC patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168146"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145835523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-04DOI: 10.1016/j.bbadis.2025.168152
Peng Du , Meng Deng , Xin Ge , Wendong Wang , Mingfang Zhang , Panliang Wang
Background
Ischemia-reperfusion injury (IRI) represents a significant and unavoidable clinical challenge in donation after cardiac death (DCD) liver transplantation. Excessive sterile inflammation plays a critical role in the pathogenesis of liver IRI. This study, guided by bioinformatics insights, investigates the function of ZFP36 ring finger protein like 1 (ZFP36L1) in the activation of Kupffer cells (KCs) in IRI in DCD liver transplantation.
Methods
A rat DCD liver transplantation model and a lipopolysaccharide (LPS)-induced KCs inflammation model were established. Models were pretreated with ZFP36L1 and/or PR/SET domain 1 (PRDM1) gene overexpression vectors for functional and mechanistic examination.
Results
ZFP36L1 was downregulated in KCs in both the rats with the DCD liver transplantation model and human DCD liver transplantation specimens. Overexpression of ZFP36L1 in rat KCs ameliorated liver injury, reduced the secretion of inflammatory cytokines, alleviated oxidative stress, inhibited cell apoptosis, and suppressed the inflammatory activation of KCs. Parallel anti-inflammatory effects of ZFP36L1 were observed in LPS-treated mouse KCs in vitro. As an RNA-binding protein, ZFP36L1 promoted the degradation of PRDM1 mRNA by specifically binding to AU-rich elements within its 3′-untranslated region (3′-UTR). Overexpression of PRDM1 effectively counteracted the regulatory effects of ZFP36L1, thereby reversing the suppression of inflammatory activation in KCs and exacerbating liver IRI.
Conclusion
This study demonstrates that ZFP36L1 mitigates the inflammatory activation of KCs and alleviates DCD liver IRI by inducing PRDM1 mRNA degradation.
{"title":"ZFP36L1-mediated PRDM1 mRNA degradation inhibits inflammatory activation of Kupffer cells and ameliorates DCD liver ischemic-reperfusion injury","authors":"Peng Du , Meng Deng , Xin Ge , Wendong Wang , Mingfang Zhang , Panliang Wang","doi":"10.1016/j.bbadis.2025.168152","DOIUrl":"10.1016/j.bbadis.2025.168152","url":null,"abstract":"<div><h3>Background</h3><div>Ischemia-reperfusion injury (IRI) represents a significant and unavoidable clinical challenge in donation after cardiac death (DCD) liver transplantation. Excessive sterile inflammation plays a critical role in the pathogenesis of liver IRI. This study, guided by bioinformatics insights, investigates the function of ZFP36 ring finger protein like 1 (ZFP36L1) in the activation of Kupffer cells (KCs) in IRI in DCD liver transplantation.</div></div><div><h3>Methods</h3><div>A rat DCD liver transplantation model and a lipopolysaccharide (LPS)-induced KCs inflammation model were established. Models were pretreated with ZFP36L1 and/or PR/SET domain 1 (PRDM1) gene overexpression vectors for functional and mechanistic examination.</div></div><div><h3>Results</h3><div>ZFP36L1 was downregulated in KCs in both the rats with the DCD liver transplantation model and human DCD liver transplantation specimens. Overexpression of ZFP36L1 in rat KCs ameliorated liver injury, reduced the secretion of inflammatory cytokines, alleviated oxidative stress, inhibited cell apoptosis, and suppressed the inflammatory activation of KCs. Parallel anti-inflammatory effects of ZFP36L1 were observed in LPS-treated mouse KCs <em>in vitro</em>. As an RNA-binding protein, ZFP36L1 promoted the degradation of PRDM1 mRNA by specifically binding to AU-rich elements within its 3′-untranslated region (3′-UTR). Overexpression of PRDM1 effectively counteracted the regulatory effects of ZFP36L1, thereby reversing the suppression of inflammatory activation in KCs and exacerbating liver IRI.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that ZFP36L1 mitigates the inflammatory activation of KCs and alleviates DCD liver IRI by inducing PRDM1 mRNA degradation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168152"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-12DOI: 10.1016/j.bbadis.2025.168136
Shengnan Li , Yanyi Tan , Jiayi Tong , Xuan Xu
Activator Protein-1 (AP-1) is a dimeric transcription factor complex formed by dynamic combinations of members from the Jun, Fos, ATF, and MAF families. It plays a pivotal role in regulating cell-state decisions, including proliferation, apoptosis, differentiation, and inflammation. In the cardiovascular system, aberrant activation of AP-1 has been closely linked to pathological conditions such as atherosclerosis, cardiac hypertrophy, ischemia-reperfusion injury, and heart failure. Its functional outcomes are highly dependent on subunit composition, cell type specificity, upstream signaling, and the integration of microenvironmental signals. This review systematically explores the dynamic regulatory networks of AP-1 across distinct cardiac cell subsets, including cardiomyocytes, vascular smooth muscle cells, cardiac fibroblasts, cardiac endothelial cells, and cardiac macrophages. Emerging evidence highlights the multifaceted, spatiotemporally tuned, and cell-type-specific roles of AP-1 in cardiovascular pathology. Future studies leveraging single-cell multi-omics and epigenetic profiling will be essential to elucidate the precise mechanisms of AP-1 action in individual cell types, and to refine therapeutic strategies targeting AP-1, thereby offering novel insights into precision medicine for cardiovascular diseases.
{"title":"The role of AP-1 in distinct cardiac cell types: Pathological repair and maladaptive remodeling","authors":"Shengnan Li , Yanyi Tan , Jiayi Tong , Xuan Xu","doi":"10.1016/j.bbadis.2025.168136","DOIUrl":"10.1016/j.bbadis.2025.168136","url":null,"abstract":"<div><div>Activator Protein-1 (AP-1) is a dimeric transcription factor complex formed by dynamic combinations of members from the Jun, Fos, ATF, and MAF families. It plays a pivotal role in regulating cell-state decisions, including proliferation, apoptosis, differentiation, and inflammation. In the cardiovascular system, aberrant activation of AP-1 has been closely linked to pathological conditions such as atherosclerosis, cardiac hypertrophy, ischemia-reperfusion injury, and heart failure. Its functional outcomes are highly dependent on subunit composition, cell type specificity, upstream signaling, and the integration of microenvironmental signals. This review systematically explores the dynamic regulatory networks of AP-1 across distinct cardiac cell subsets, including cardiomyocytes, vascular smooth muscle cells, cardiac fibroblasts, cardiac endothelial cells, and cardiac macrophages. Emerging evidence highlights the multifaceted, spatiotemporally tuned, and cell-type-specific roles of AP-1 in cardiovascular pathology. Future studies leveraging single-cell multi-omics and epigenetic profiling will be essential to elucidate the precise mechanisms of AP-1 action in individual cell types, and to refine therapeutic strategies targeting AP-1, thereby offering novel insights into precision medicine for cardiovascular diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168136"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145758769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HECW2 is a ubiquitin ligase associated with neurodevelopment, and a synapse-related target of CSDE1.
•
The E3 ligase activity of HECW2 is necessary for the downregulation of Dicer protein, a core component in the miRNA pathway that dictates miRNA expression.
{"title":"De novo CSDE1 missense variant T595N regulates miRNA expression in a patient with a complex neurodevelopmental condition","authors":"Claire Hynes , Evan Williams , Doriana Misceo , Petter Strømme , Eirik Frengen , Pavan Kumar Kakumani","doi":"10.1016/j.bbadis.2025.168104","DOIUrl":"10.1016/j.bbadis.2025.168104","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>Loss of function variants in CSDE1 have been identified in patients with neurodevelopmental disorders.</div></span></li><li><span>•</span><span><div><em>De novo</em> CSDE1 missense variant T595N was identified in an individual manifesting autistic behavior in addition to features typical of Cohen syndrome.</div></span></li><li><span>•</span><span><div>Patient derived skin fibroblasts expressing T595N showed increased expression of HECW2.</div></span></li><li><span>•</span><span><div>HECW2 is a ubiquitin ligase associated with neurodevelopment, and a synapse-related target of CSDE1.</div></span></li><li><span>•</span><span><div>The E3 ligase activity of HECW2 is necessary for the downregulation of Dicer protein, a core component in the miRNA pathway that dictates miRNA expression.</div></span></li></ul></div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168104"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145479111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-21DOI: 10.1016/j.bbadis.2025.168145
Jiancheng Mou , Hongchao Tang , Xiaoge Hu , Zhuotao Yang , Haotian Su , Da Qian , Chenhong Li , Haotian Liu , Zhihao Ye , Mingxing Xu , Shuyan Liu , Qinghui Zheng , Xiaozhen Liu , Xin Zeng , Qiuran Xu , Xuli Meng
Background
Breast cancer (BC) remains one of the major threats to women's health in the 21st century, due to its high incidence and mortality rates. Ubiquitin-conjugating enzymes, as members of the ubiquitin-proteasome system, are responsible for numerous cellular physiological processes. However, ubiquitin-conjugating enzymes may also play unexpected roles in other physiological activities, such as phosphorylation, lactylation, and even methylation. The physiological function of the ubiquitin-conjugating E2 enzyme UBE2K in BC remains unknown. As a result, we looked into UBE2K's physiological role in the malignant development of BC.
Methods
A combination of RT-qPCR, Transwell migration assays, Western blotting, and CCK-8 analysis was employed to confirm the upregulation of UBE2K in BC cells and to assess its role in promoting cell proliferation and migration. Furthermore, using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, we identified and validated CREB1 as a transcription factor for UBE2K for the first time.
Results
We discovered that UBE2K regulates the physiological processes of BC cells via the STUB1/PKA/CREB1/p-CREB1 axis. Moreover, functional rescue experiments ultimately displayed that UBE2K promotes the malignant progression of BC cells by via STUB1/PKA/CREB1/p-CREB1 axis.
Conclusions
In conclusion, the UBE2K/CREB1 positive feedback loop promotes the development of BC, indicating that UBE2K could be a viable therapeutic target for anti-BC.
{"title":"UBE2K promotes breast cancer growth by ubiquitinating and degrading STUB1 to regulate the PKA/CREB1 signaling pathway, forming a feedback loop","authors":"Jiancheng Mou , Hongchao Tang , Xiaoge Hu , Zhuotao Yang , Haotian Su , Da Qian , Chenhong Li , Haotian Liu , Zhihao Ye , Mingxing Xu , Shuyan Liu , Qinghui Zheng , Xiaozhen Liu , Xin Zeng , Qiuran Xu , Xuli Meng","doi":"10.1016/j.bbadis.2025.168145","DOIUrl":"10.1016/j.bbadis.2025.168145","url":null,"abstract":"<div><h3>Background</h3><div>Breast cancer (BC) remains one of the major threats to women's health in the 21st century, due to its high incidence and mortality rates. Ubiquitin-conjugating enzymes, as members of the ubiquitin-proteasome system, are responsible for numerous cellular physiological processes. However, ubiquitin-conjugating enzymes may also play unexpected roles in other physiological activities, such as phosphorylation, lactylation, and even methylation. The physiological function of the ubiquitin-conjugating E2 enzyme UBE2K in BC remains unknown. As a result, we looked into UBE2K's physiological role in the malignant development of BC.</div></div><div><h3>Methods</h3><div>A combination of RT-qPCR, Transwell migration assays, Western blotting, and CCK-8 analysis was employed to confirm the upregulation of UBE2K in BC cells and to assess its role in promoting cell proliferation and migration. Furthermore, using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, we identified and validated CREB1 as a transcription factor for UBE2K for the first time.</div></div><div><h3>Results</h3><div>We discovered that UBE2K regulates the physiological processes of BC cells via the STUB1/PKA/CREB1/p-CREB1 axis. Moreover, functional rescue experiments ultimately displayed that UBE2K promotes the malignant progression of BC cells by via STUB1/PKA/CREB1/p-CREB1 axis.</div></div><div><h3>Conclusions</h3><div>In conclusion, the UBE2K/CREB1 positive feedback loop promotes the development of BC, indicating that UBE2K could be a viable therapeutic target for anti-BC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168145"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-09DOI: 10.1016/j.bbadis.2025.168133
Rong Xu , Xiu-wen Liang , Qi-hai Cai , Yuan-wen Cai , Nuo Sun , Ya-ping Li , Zi-jian Shi , Bo Hu , Xian-hui He , Qing-bing Zha , Dong-yun Ouyang
Hyperthermia induces heat stress (HS) and injuries in various human organs, or even leads to mortality, yet the underlying mechanism is incompletely uncovered. Our study revealed that HS in macrophages induced concurrent activation of pyroptotic, apoptotic, and necroptotic pathways, and the formation of PANoptosome-like complexes. However, these processes proceeded independently of ROS, as the ROS scavengers N-acetyl cysteine and mito-TEMPO failed to prevent the cell death (PANoptosis) despite effectively suppressing oxidative stress. Instead, HS caused reductive stress marked by NADPH accumulation and thioredoxin (Trx) system dysfunction. Trx1 aggregation impaired redox regulation, leading to aberrant disulfide bonding in mitochondrial proteins (e.g., Drp1, Bcl-2). The Trx reductase exogenous substrate DTNB partially rescued cell viability by restoring redox balance, confirming Trx failure as a key driver of cytotoxicity. Notably, such reductive stress was accompanied by DNA damage and mitochondrial injury during HS. Pharmacologic intervention revealed that pan-caspase inhibition by IDN-6556 abrogated the reductive stress and its consequences (ROS production, DNA damage, and mitochondrial injury), and suppressed the pyroptotic/apoptotic signaling and lytic cell death. However, the caspase inhibition alone triggered compensatory receptor-interaction protein 3 (RIPK3) activation, necessitating dual inhibition with GSK’872 (RIPK3 inhibitor) to fully block PANoptotic cell death. In vivo validation showed protection of the IDN-6556/GSK′872 combination against HS-induced injury on the intestines through reduced DNA damage and PANoptosis suppression. Our study reveals that reductive stress-mediated Trx dysfunction, not oxidative stress, underlies HS-induced PANoptosis. Dual targeting of caspases and RIPK3 provides a novel therapeutic avenue against heat shock-associated diseases.
{"title":"Hyperthermia induces reductive stress in murine macrophages","authors":"Rong Xu , Xiu-wen Liang , Qi-hai Cai , Yuan-wen Cai , Nuo Sun , Ya-ping Li , Zi-jian Shi , Bo Hu , Xian-hui He , Qing-bing Zha , Dong-yun Ouyang","doi":"10.1016/j.bbadis.2025.168133","DOIUrl":"10.1016/j.bbadis.2025.168133","url":null,"abstract":"<div><div>Hyperthermia induces heat stress (HS) and injuries in various human organs, or even leads to mortality, yet the underlying mechanism is incompletely uncovered. Our study revealed that HS in macrophages induced concurrent activation of pyroptotic, apoptotic, and necroptotic pathways, and the formation of PANoptosome-like complexes. However, these processes proceeded independently of ROS, as the ROS scavengers <em>N</em>-acetyl cysteine and mito-TEMPO failed to prevent the cell death (PANoptosis) despite effectively suppressing oxidative stress. Instead, HS caused reductive stress marked by NADPH accumulation and thioredoxin (Trx) system dysfunction. Trx1 aggregation impaired redox regulation, leading to aberrant disulfide bonding in mitochondrial proteins (<em>e.g.</em>, Drp1, Bcl-2). The Trx reductase exogenous substrate DTNB partially rescued cell viability by restoring redox balance, confirming Trx failure as a key driver of cytotoxicity. Notably, such reductive stress was accompanied by DNA damage and mitochondrial injury during HS. Pharmacologic intervention revealed that pan-caspase inhibition by IDN-6556 abrogated the reductive stress and its consequences (ROS production, DNA damage, and mitochondrial injury), and suppressed the pyroptotic/apoptotic signaling and lytic cell death. However, the caspase inhibition alone triggered compensatory receptor-interaction protein 3 (RIPK3) activation, necessitating dual inhibition with GSK’872 (RIPK3 inhibitor) to fully block PANoptotic cell death. <em>In vivo</em> validation showed protection of the IDN-6556/GSK′872 combination against HS-induced injury on the intestines through reduced DNA damage and PANoptosis suppression. Our study reveals that reductive stress-mediated Trx dysfunction, not oxidative stress, underlies HS-induced PANoptosis. Dual targeting of caspases and RIPK3 provides a novel therapeutic avenue against heat shock-associated diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168133"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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