Molecular and Cellular Biochemistry最新文献

{"title":"Eugenol regulates ferroptosis through Mfn2/SLC7A11/GPX4 pathway to alleviate glutamate excitotoxicity damage in glaucoma.","authors":"Qian Wang, Lemeng Feng, Cheng Zhang, Weiming Zhu, Min He, Fangbing Ye, Longqing Luo, Shiqi Qin, Zhiqi Xiong, Haifa Liu, Weitao Song, Yu Xiong","doi":"10.1007/s11010-026-05676-x","DOIUrl":"10.1007/s11010-026-05676-x","url":null,"abstract":"<p><p>Glaucoma is a leading cause of irreversible blindness, characterized by progressive loss of retinal ganglion cells (RGCs), with glutamate excitotoxicity being a key contributor to RGC damage. Eugenol, a natural phenolic compound, has been shown to exhibit neuroprotective properties. However, protective effect of eugenol on glaucoma has not been explored. This study aimed to evaluate neuroprotective effects of eugenol in models of glutamate excitotoxicity and to explore the underlying mechanisms. The glutamate-induced R28 cell excitotoxicity model and N-methyl-D-aspartate (NMDA)-induced mouse glaucoma model were established. Cell Counting Kit-8 (CCK-8), iron ion probes, lipid peroxidation detection and other techniques were employed to elucidate whether eugenol could alleviate glutamate-induced ferroptosis. Subsequently, in vivo validation was performed using C57BL/6J mice. Eugenol significantly attenuated glutamate-induced R28 cell death and RGC damage. Eugenol restored Mitofusin 2 (Mfn2) levels reduced by glutamate excitotoxicity, thereby reducing abnormal lipid droplet (LD) accumulation and alleviating mitochondrial dysfunction. Furthermore, it upregulated solute carrier family 7 member 11 (SLC7A11), increased cellular glutathione (GSH) levels, and activated glutathione peroxidase 4 (GPX4) in an Mfn2-dependent manner, ultimately inhibiting ferroptosis. Eugenol exerts neuroprotective effects in glaucoma excitotoxicity models by suppressing ferroptosis through Mfn2-mediated regulation of mitochondrial-LD homeostasis and the SLC7A11/GSH/GPX4 antioxidant pathway.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4465-4481"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148630922","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}

{"title":"Ckmm-Cre transgenic mice maintain phenotypic and cardiac mitochondrial homeostasis during ketogenic feeding.","authors":"Sukru Anil Dogan","doi":"10.1007/s11010-026-05672-1","DOIUrl":"10.1007/s11010-026-05672-1","url":null,"abstract":"<p><p>Conditional gene targeting using the Cre-loxP system requires validation of each Cre driver line under the specific experimental conditions to be employed, as Cre recombinase expression can cause transgene-associated pathology. The Ckmm-Cre transgenic mouse is widely used for heart- and skeletal muscle-directed conditional gene targeting, yet its phenotypic and cardiac mitochondrial response to ketogenic diet (KD) remains uncharacterized. Here we report that four-week KD feeding did not alter body weight, treadmill endurance, grip strength, locomotor activity, or rotarod performance in young male Ckmm-Cre mice. Cardiac mitochondrial oxygen consumption and hydrogen peroxide production, assessed by high-resolution respirometry, were likewise unchanged. In cardiac tissue lysates, oxidative phosphorylation subunit abundance and VDAC1 levels were maintained, with no major diet-associated changes in mitochondrial protein content. These pilot data establish a baseline reference for future conditional knockout studies employing this Cre driver under ketogenic conditions.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4355-4362"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620842","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}

{"title":"NEK2 is essential for spindle assembly checkpoint regulation and cytoskeleton organization in porcine oocyte meiotic maturation.","authors":"Se-Been Jeon, Pil-Soo Jeong, Hyo-Gu Kang, Ji Hyeon Yun, Se-Yeon Eom, Na-Gyeom Oh, Yeounsun Oh, Seung Hwan Lee, Sun-Uk Kim, Seong-Keun Cho, Bo-Woong Sim","doi":"10.1007/s11010-026-05674-z","DOIUrl":"10.1007/s11010-026-05674-z","url":null,"abstract":"<p><p>NIMA-related kinase 2 (NEK2) is a serine/threonine kinase that plays crucial roles in cellular events such as centrosome separation, cell cycle progression, spindle assembly checkpoint (SAC) regulation, and microtubule stabilization. However, its regulatory function during oocyte meiotic maturation remains unclear. In this study, NEK2 activity was inhibited using the specific inhibitor MBM-55 to evaluate its role in oocyte meiotic maturation and early embryonic development. NEK2 depletion impaired multiple indicators associated with oocyte maturation and decreased the maturation rate. Mechanistic analysis suggested that NEK2 inhibition altered spindle organization and chromosome alignment, which may be associated with impaired kinetochore-microtubule (K-MT) interactions and altered SAC-associated signaling, collectively contributing to MI-stage arrest and increased aneuploidy. In addition, NEK2 deficiency impaired the actin network, reducing spindle migration, preventing the efficient repair of accumulated DNA damage and ultimately leading to apoptosis. NEK2 inhibition in oocytes reduced subsequent embryonic developmental competence, leading to a lower blastocyst formation rate. These findings demonstrate that NEK2 is a critical regulator of porcine oocyte meiotic maturation through its roles in SAC regulation, K-MT attachment, cytoskeletal dynamics, and the DNA damage response.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4549-4564"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IRP1 deficiency promotes fibroblast activation through iron dysregulation: protective modulation by H₂S.","authors":"Anmol Bola, Alex McFadden, Oyine Favour Ochigbo, Hassan Mustafa Arif, Rui Wang, Kostas Pantopoulos, Guangdong Yang","doi":"10.1007/s11010-026-05698-5","DOIUrl":"10.1007/s11010-026-05698-5","url":null,"abstract":"<p><p>Iron is indispensable for core physiological processes, and intracellular iron homeostasis is tightly governed by iron regulatory protein 1 (IRP1). Hydrogen sulfide (H₂S), an endogenous gasotransmitter with well-established antioxidant and cytoprotective activities, remains poorly characterized for its regulatory roles in IRP1-dependent iron metabolism and fibroblast activation. Herein, we employed primary mouse embryonic fibroblasts (MEFs) to interrogate the functional crosstalk between NaHS (a H₂S donor) and IRP1 governing iron balance and profibrotic responses. Our results reveal that IRP1 ablation or iron supplementation elevates the labile iron pool, triggers oxidative stress, and enhances cell adhesion, proliferation, and expression of profibrotic genes. Exogenous NaHS supplementation reduced labile iron accumulation and rescued iron-evoked cellular abnormalities, with this beneficial effect predominantly observed in wild-type MEFs. Mechanistically, NaHS upregulated IRP1 aconitase activity without altering the expression of transferrin receptor 1 or ferritin heavy chain. Although IRP1 deficiency and iron overload boosted endogenous H₂S production, neither manipulation changed the protein abundance of three major H₂S-synthesizing enzymes: cystathionine gamma-lyase (CSE), cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase. In vivo, intravenous iron administration elicited markedly greater cardiac profibrotic gene expression in CSE-knockout mice relative to wild-type littermates. Taken together, these data establish that H₂S mitigates iron overload and subsequent fibrosis driven by IRP1 dysfunction, pointing toward promising therapeutic strategies for iron imbalance-associated fibrotic disorders.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4723-4737"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706983","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}

{"title":"Long-chain chlorinated paraffins exposure induces premature ovarian failure by disrupting the balance of mitochondrial fission.","authors":"Chenhui Xu, Haochu Deng, Xue Tian, Shuang Ma, Yuebing Kong, Ruoting Zhang, Shiyu Yao, Hainan Lan","doi":"10.1007/s11010-026-05696-7","DOIUrl":"10.1007/s11010-026-05696-7","url":null,"abstract":"<p><p>Long-chain chlorinated paraffins (LCCPs) accumulate in reproductive organs due to their high persistence and bioaccumulation potential; however, the molecular mechanisms underlying their ovarian toxicity remain unclear. In this study, we used primary mouse granulosa cells, a human SVOG cell line, and an oral exposure model in female mice to systematically evaluate the ovarian damage effects of LCCPs and investigate the underlying signaling pathways. The results showed that concentrations of 0.02-2 µg/mL of LCCPs concentration-dependently reduced granulosa cell survival rates (by 12%-58%, P < 0.05), while significantly upregulating oxidative stress (MDA, ROS), inflammatory cytokines (IL-6, TNF-α), and aging markers (SA-β-gal activity). In vivo exposure led to morphological degeneration of ovarian tissue and a reduction in the number of primordial follicles, accompanied by decreased serum estradiol and elevated follicle-stimulating hormone (FSH) levels; these changes resemble the phenotype of clinical ovarian dysfunction. At the mechanistic level, LCCPs induce excessive mitochondrial fission by blocking the interaction between Drp1 and Parkin, leading to the leakage of mitochondrial DNA into the cytoplasm, which in turn activates the cGAS-STING pathway and ultimately drives granulosa cell senescence. These findings reveal a novel mechanism by which LCCPs mediate ovarian toxicity via the \"excessive mitochondrial fragmentation- mtDNA leakage- cGAS- STING- cellular senescence\" axis, providing direct experimental evidence for assessing the risks of persistent organic pollutants to female reproductive health.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4813-4828"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795529","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}

{"title":"Anemoside B4 upregulates DDAH2 and attenuates oxidative stress induced endothelial dysfunction.","authors":"Shuxian Lu, Yao Yi, Qin Chen, Luling He, Margaret Baldini, Dan Shan, Limin Gong, Liang Qiu, Shumin Ma, Manman Qin, Yanyun Fang, Yifeng Zhang, Jun Yu","doi":"10.1007/s11010-026-05690-z","DOIUrl":"10.1007/s11010-026-05690-z","url":null,"abstract":"<p><p>Endothelial dysfunction, involving diminished nitric oxide (NO) bioavailability and vascular inflammation, plays a pivotal role in cardiovascular disease progression. Anemoside B4 (AB4), a major bioactive component extracted from Pulsatilla chinensis, has been reported to exert anti-inflammatory, anti-tumor, and antiviral effects. However, its potential role in regulating endothelial function remains largely unexplored. Integrating RNA-seq analysis, we revealed that AB4 may exert anti-atherosclerotic effects by upregulating DDAH2 expression and improving endothelial NO production. Using an H₂O₂-induced endothelial cell dysfunction model, we found that AB4 significantly reversed H₂O₂-induced impairments in endothelial cell viability and migration, while attenuating apoptosis and reducing monocyte adhesion. In addition, AB4 upregulated DDAH2 protein expression, restored eNOS phosphorylation, and increased NO production under oxidative stress conditions. Pharmacological perturbation of DDAH2 protein expression with PD404182 attenuated the AB4-mediated restoration of eNOS-NO signaling and weakened its inhibitory effects on monocyte-endothelial adhesion and ICAM-1/VCAM-1 expression. Consistently, in a mouse model of oxidative stress-induced endothelial dysfunction, AB4 increased endothelial DDAH2 protein expression, enhanced NO production, and suppressed endothelial ICAM-1 and VCAM-1 expression. These effects were attenuated by PD404182, supporting the involvement of DDAH2 regulation in the endothelial protective effects of AB4. Taken together, these results suggest that AB4 restores endothelial eNOS-NO signaling and counteracts oxidative stress-induced endothelial dysfunction, evidenced by enhanced viability, improved migration, and reduced apoptosis and inflammation, with these effects being associated with DDAH2 upregulation.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4857-4871"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795435","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}

{"title":"Erastin-sensitive VDAC2 contributes to time-course peritoneal fibrosis via ferroptosis signaling induction.","authors":"Wenfeng Wei, Yanping Qiu, Rong Luo, Yangping Feng","doi":"10.1007/s11010-026-05694-9","DOIUrl":"10.1007/s11010-026-05694-9","url":null,"abstract":"<p><p>Peritoneal dialysis (PD) is a renal replacement therapy for patients with end-stage renal disease, but long-term treatment often leads to peritoneal fibrosis, compromising dialysis efficacy. This study aimed to elucidate the role of ferroptosis in peritoneal fibrosis (PF) and to clarify the regulatory function of the voltage-dependent anion channel 2 (VDAC2). Mesothelial cell subpopulations were identified from the single-cell dataset GSE130888, followed by differential gene expression analysis to screen ferroptosis-related genes. In vitro and in vivo models were used to validate the involvement of ferroptosis in PF. siRNA-mediated VDAC2 knockdown, combined with the ROS scavenger NAC, was applied to assess its role in regulating mitochondrial ROS during ferroptosis and fibrosis. Single-cell analysis revealed ferroptosis-related gene alterations in both short-term (ST) and long-term (LT) PD, with VDAC2 expression positively associated with dialysis duration. Erastin significantly reduced MET‑5 A cell viability, increased apoptosis, elevated ROS and lipid peroxidation, decreased GSH levels, and upregulated VDAC2, ACSL4, and fibrosis‑related proteins. These effects were reversed by Fer‑1. In vivo, Erastin exacerbated peritoneal dysfunction, collagen deposition, and tissue iron accumulation in mice, and caused complete collapse of cellular architecture, dissolution of organelles, nuclear envelope rupture, and chromatin fragmentation, whereas Fer‑1 improved peritoneal pathology and iron deposition. VDAC2 knockdown restored MET‑5 A cell viability, reduced ROS and lipid peroxidation, increased GSH levels, and downregulated ferroptosis- and fibrosis-related proteins; co‑treatment with NAC further enhanced these protective effects. VDAC2 promotes peritoneal mesothelial cell injury and fibrosis by driving mitochondrial ROS-dependent ferroptosis. Targeting VDAC2 or inhibiting ferroptosis may provide a potential therapeutic strategy to delay peritoneal dialysis-associated fibrosis.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4829-4842"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795477","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}

{"title":"Actin polymerization drives endogenous MMP-9 upregulation and blood-brain barrier disruption in ischemic brain endothelial cells.","authors":"Yiyin Zhao, Songbin He, Yiming Wang, Meng Jin, Yichao Fu, Xiaojing Zhou","doi":"10.1007/s11010-026-05706-8","DOIUrl":"10.1007/s11010-026-05706-8","url":null,"abstract":"<p><p>Blood-brain barrier (BBB) disruption is a critical early event in ischemic stroke. Matrix metalloproteinase-9 (MMP-9) drives BBB breakdown through proteolytic degradation of junctional proteins; however, the upstream mechanisms triggering endogenous MMP-9 upregulation within brain endothelial cells before inflammatory cell infiltration remain poorly understood. Here, we identify actin polymerization as a functional upstream driver of endothelial MMP-9 activation and BBB disruption under ischemic conditions. Using an oxygen-glucose deprivation (OGD) model in bEnd.3 cells, we found that 6 h of OGD induced significant actin remodeling concurrent with upregulation of both MMP-9 expression and enzymatic activity, reduced the total protein levels of occludin, ZO-1, and VE-cadherin, disrupted their membrane localization, and increased transendothelial permeability. Bidirectional pharmacological modulation of actin dynamics using jasplakinolide (an F-actin stabilizer) and latrunculin B (a polymerization inhibitor) correspondingly amplified or attenuated all these changes. Crucially, lentivirus-mediated shRNA knockdown of MMP-9 significantly preserved junctional protein expression, maintained transendothelial electrical resistance, and reduced barrier permeability even under jasplakinolide-enhanced polymerization, establishing MMP-9 as a necessary mediator of actin-driven barrier disruption. MMP-9 knockdown also attenuated F-actin accumulation, suggesting a self-amplifying feedback loop. These findings delineate an endothelial-autonomous actin-MMP-9-BBB disruption axis that operates independently of inflammatory cell infiltration, identifying endothelial actin homeostasis as a potential therapeutic target for early barrier protection in ischemic stroke.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4987-5007"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840740","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}

{"title":"Quercetin exerts radioprotective effects against radiation-induced intestinal injury with involvement of the PI3K-AKT/Caspase-3 axis.","authors":"Qing Guo, Zhibing Tang, Zhenyu Hou, Ge Yan, Jiaxuan Wang, Man Zhang, Ruige Ma, Juan Wang, Qiong Feng, Zhen Wang, Chunlei Wang, Lin Zhao","doi":"10.1007/s11010-026-05665-0","DOIUrl":"10.1007/s11010-026-05665-0","url":null,"abstract":"<p><p>Radiation-induced intestinal injury (RIII) significantly limits the efficacy of abdominal and pelvic radiotherapy while also impairing patient quality of life. This condition is primarily driven by excessive reactive oxygen species (ROS) and dysregulation of Caspase-dependent apoptosis. Quercetin (QUE), a natural antioxidant flavonoid, exhibits radioprotective potential; however, the key signaling pathways it employs to regulate radiation-induced apoptosis remain to be elucidated. In vitro studies, IEC-6 cells (1-10 µg/mL QUE pretreatment followed by 0-8 Gy X-ray exposure) were conducted to analyze proliferation, clonogenic survival, ROS levels, apoptosis, and expression of RIII-related proteins and genes. Network pharmacology identified 47 overlapping targets associated with QUE and RIII, with AKT1 and CASP3 identified as hub targets, and the PI3K-AKT pathway recognized as a key regulatory pathway. A Caspase-3/7 inhibitor (HY-103346, H10) and AutoDock-Vina docking analysis were used to explore the involvement of Caspase-3-related apoptotic signaling. In vivo experiments using Drosophila melanogaster (W¹¹¹⁸) involved groups subjected to control, 50 Gy irradiation alone, or 50 Gy combined with 1/5/10/50 µg/mL QUE. Lifespan, locomotor capacity, and intestinal ROS levels were assessed, including validation with DCP-1^RNAi transgenic flies (DCP-1: Drosophila Caspase-3 homolog). In vitro findings revealed that QUE enhanced the viability of irradiated IEC-6 cells, reduced ROS and apoptosis, upregulated anti-apoptotic markers (p-AKT, p-PI3K and p-mTOR), and downregulated pro-apoptotic markers (cleaved-Caspase-3 and Cytochrome C), while H10 inhibited the effects of QUE. Molecular docking suggested a potential interaction between QUE and Caspase-3 through hydrogen bonds and hydrophobic interactions to inhibit its activation. In vivo, pre-irradiation gavage of 10 µg/mL QUE mitigated RIII in Drosophila, an effect that was abolished in DCP-1 knockdown flies. In summary, QUE protects against RIII by scavenging ROS and modulating apoptosis-related signaling, with evidence supporting the involvement of the PI3K-AKT/Caspase-3 axis, with the PI3K-AKT/Caspase-3 axis identified as central to these protective effects. This study underscores the clinical potential of QUE for RIII and offers insights into the targeting of apoptosis for radioprotection.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4337-4354"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620800","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}

{"title":"Trimethylamine N-oxide activates cardiac fibroblasts transformation through NLRP3 inflammasome activation with changes in mitochondrial dynamics and ER-mitochondrial contact under ER stress.","authors":"Huimin Wang, Hanlin Liu, Xinnan Meng, Jiantao Song, Yan Jin, Yuanyuan Bai","doi":"10.1007/s11010-026-05658-z","DOIUrl":"10.1007/s11010-026-05658-z","url":null,"abstract":"<p><p>Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been linked to cardiovascular diseases. This study aimed to explore the role of TMAO in cardiac fibrosis by examining its effects on the NLRP3 inflammasome, endoplasmic reticulum stress (ERS), mitochondria-associated membranes (MAMs), and mitochondrial dynamics in cardiac fibroblasts (CFs), alongside clinical data from acute myocardial infarction (AMI) patients and unstable angina (UA) patients and AMI animal model data. Plasma TMAO levels were measured in AMI patients and healthy controls. In vitro, CFs were treated with TMAO to assess cellular activation and fibrosis markers. Western blot, immunofluorescence, and RNA sequencing identified key pathways and proteins related to ERS, NLRP3 inflammasome activation, and mitochondrial dynamics. In vivo, Masson's trichrome staining, Hematoxylin-Eosin (HE) staining and Immunohistochemical were used to evaluate the effects of TMAO on AMI mice. Plasma TMAO levels were significantly higher in the AMI group. TMAO promoted cardiac fibroblast activation and fibrosis by increasing α-SMA and Collagen I expression. It induced ERS, marked by elevated GRP78, p-PERK, and CHOP, and upregulated Sigma-1R, enhancing MAM formation. TMAO also altered mitochondrial dynamics via DRP1 phosphorylation and Mfn2 expression. RNA sequencing identified macrophage migration inhibitory factor (MIF) as a key mediator linking TMAO to NLRP3 inflammasome activation. TMAO exacerbates myocardial injury and fibrotic remodeling in AMI mice. TMAO exacerbates cardiac fibrosis via ERS and NLRP3 activation, with implications for mitochondrial dynamics and MAM formation. Elevated TMAO levels in AMI patients underscore its potential as a therapeutic target for ventricular remodeling fibrosis.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4157-4180"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520755","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}