Pub Date : 2025-11-14DOI: 10.1016/j.bbadis.2025.168119
Yan Su , Lingqi Kong , Bowen Xue , Peng Shi , Sheng Cai , Yang Xu , Xianwen Chen , Hongdang Qu
Background
Increasing evidence suggests that ferroptosis has significant implications for the pathogenesis of vascular dementia (VaD). Although KLKB1 exacerbates neurological damage in VaD by promoting ferroptosis, the exact mechanism remains unclear. The aim of this study is to elucidate the specific pathway through which KLKB1 mediates ferroptosis in VaD and to identify effective therapeutic strategies.
Methods
Rat models of VaD were constructed by bilateral common carotid artery occlusion (BCCAO). Behavioral impairment in VaD rats was assessed, along with pathological damage to hippocampal neurons. Transcriptome sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blotting, and quantitative real-time polymerase chain reaction (qPCR) were used to identify the downstream pathways through which KLKB1 regulates ferroptosis. Immunoprecipitation–mass spectrometry (IP–MS), protein–protein interaction networks, coimmunoprecipitation (Co-IP), and immunofluorescence assays were used to screen for proteins that interact with KLKB1.
Results
KLKB1 promotes ferroptosis in VaD model rats through its interaction with transcription factor E3 (TFE3). The knockdown of KLKB1 decreased TFE3 expression levels and suppressed ferroptosis through the inhibition of the BRaf/MEK/ERK signaling cascade. Consistent antiferroptotic effects were observed following TFE3 knockdown.
Conclusion
The KLKB1–TFE3–BRaf/MEK/ERK signaling axis represents a novel target for attenuating ferroptosis in VaD.
{"title":"The KLKB1–TFE3–BRAF/MEK/ERK axis regulates neuronal ferroptosis in vascular dementia","authors":"Yan Su , Lingqi Kong , Bowen Xue , Peng Shi , Sheng Cai , Yang Xu , Xianwen Chen , Hongdang Qu","doi":"10.1016/j.bbadis.2025.168119","DOIUrl":"10.1016/j.bbadis.2025.168119","url":null,"abstract":"<div><h3>Background</h3><div>Increasing evidence suggests that ferroptosis has significant implications for the pathogenesis of vascular dementia (VaD). Although KLKB1 exacerbates neurological damage in VaD by promoting ferroptosis, the exact mechanism remains unclear. The aim of this study is to elucidate the specific pathway through which KLKB1 mediates ferroptosis in VaD and to identify effective therapeutic strategies.</div></div><div><h3>Methods</h3><div>Rat models of VaD were constructed by bilateral common carotid artery occlusion (BCCAO). Behavioral impairment in VaD rats was assessed, along with pathological damage to hippocampal neurons. Transcriptome sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blotting, and quantitative real-time polymerase chain reaction (qPCR) were used to identify the downstream pathways through which KLKB1 regulates ferroptosis. Immunoprecipitation–mass spectrometry (IP–MS), protein–protein interaction networks, coimmunoprecipitation (Co-IP), and immunofluorescence assays were used to screen for proteins that interact with KLKB1.</div></div><div><h3>Results</h3><div>KLKB1 promotes ferroptosis in VaD model rats through its interaction with transcription factor E3 (TFE3). The knockdown of KLKB1 decreased TFE3 expression levels and suppressed ferroptosis through the inhibition of the BRaf/MEK/ERK signaling cascade. Consistent antiferroptotic effects were observed following TFE3 knockdown.</div></div><div><h3>Conclusion</h3><div>The KLKB1<strong>–</strong>TFE3<strong>–</strong>BRaf/MEK/ERK signaling axis represents a novel target for attenuating ferroptosis in VaD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168119"},"PeriodicalIF":4.2,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535114","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 : 2025-11-12DOI: 10.1016/j.bbadis.2025.168108
Yaling Zhang , Yi Zhang , Daojuan Wang , Yajing Weng , Shanmei Shen , Yanting Wen , Jianguo Ruan , Yong Wang
Objective
Hyperandrogenism is a central pathological feature of polycystic ovary syndrome (PCOS) that disrupts granulosa cell function. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, may contribute to ovarian injury. This study aimed to clarify the pathways of hyperandrogenic-induced granulosa cells ferroptosis, elucidating the molecular mechanism of exercise and its secretory factor, irisin, through the NCOA4-FTH pathway.
Methods
DHEA-induced PCOS model and in vitro granulosa cells were constructed to systematically evaluate the effects of exercise and irisin on ovarian function and ferroptosis. In vivo experiments included treadmill training in PCOS mice, assessment of estrous cycles, glucose/insulin tolerance, ovarian morphology, oxidative stress, ferroptosis, and NCOA4-FTH pathway proteins. In vitro, granulosa cells were treated with DHT and co-exposed to irisin or the ferroptosis inhibitor Ferrostatin-1 (Fer-1), with siRNA-mediated NCOA4 knockdown for functional verification.
Results
DHEA-induced PCOS mice exhibited disrupted estrous cycles, abnormal follicular morphology, glucose intolerance, insulin resistance, and ferroptosis activation, characterized by oxidative stress, Fe2+ overload, and dysregulated ferroptosis-related proteins. Fer-1 reversed DHT-induced GPX4 downregulation, suggesting ferroptosis involvement. Eight-week aerobic exercise improved metabolic parameters and ovarian morphology, suppressed ferroptosis by modulating NCOA4 and GPX4 expression, and alleviated oxidative stress. Mechanistically, exercise-induced irisin inhibited ferritinophagy and restored iron metabolism via the NCOA4-FTH pathway. NCOA4 knockdown further validated its central role in regulating ferritinophagy.
Conclusion
Hyperandrogenism triggers granulosa cells ferroptosis in PCOS, while exercise and irisin protect ovarian function by regulating the NCOA4–FTH pathway, suggesting a potential therapeutic target for PCOS.
{"title":"Exercise-induced irisin attenuates ferroptosis in polycystic ovary syndrome by modulating the NCOA4-FTH pathway","authors":"Yaling Zhang , Yi Zhang , Daojuan Wang , Yajing Weng , Shanmei Shen , Yanting Wen , Jianguo Ruan , Yong Wang","doi":"10.1016/j.bbadis.2025.168108","DOIUrl":"10.1016/j.bbadis.2025.168108","url":null,"abstract":"<div><h3>Objective</h3><div>Hyperandrogenism is a central pathological feature of polycystic ovary syndrome (PCOS) that disrupts granulosa cell function. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, may contribute to ovarian injury. This study aimed to clarify the pathways of hyperandrogenic-induced granulosa cells ferroptosis, elucidating the molecular mechanism of exercise and its secretory factor, irisin, through the NCOA4-FTH pathway.</div></div><div><h3>Methods</h3><div>DHEA-induced PCOS model and in vitro granulosa cells were constructed to systematically evaluate the effects of exercise and irisin on ovarian function and ferroptosis. In vivo experiments included treadmill training in PCOS mice, assessment of estrous cycles, glucose/insulin tolerance, ovarian morphology, oxidative stress, ferroptosis, and NCOA4-FTH pathway proteins. In vitro, granulosa cells were treated with DHT and co-exposed to irisin or the ferroptosis inhibitor Ferrostatin-1 (Fer-1), with siRNA-mediated <em>NCOA4</em> knockdown for functional verification.</div></div><div><h3>Results</h3><div>DHEA-induced PCOS mice exhibited disrupted estrous cycles, abnormal follicular morphology, glucose intolerance, insulin resistance, and ferroptosis activation, characterized by oxidative stress, Fe<sup>2+</sup> overload, and dysregulated ferroptosis-related proteins. Fer-1 reversed DHT-induced <em>GPX4</em> downregulation, suggesting ferroptosis involvement. Eight-week aerobic exercise improved metabolic parameters and ovarian morphology, suppressed ferroptosis by modulating <em>NCOA4</em> and <em>GPX4</em> expression, and alleviated oxidative stress. Mechanistically, exercise-induced irisin inhibited ferritinophagy and restored iron metabolism via the NCOA4-FTH pathway. <em>NCOA4</em> knockdown further validated its central role in regulating ferritinophagy.</div></div><div><h3>Conclusion</h3><div>Hyperandrogenism triggers granulosa cells ferroptosis in PCOS, while exercise and irisin protect ovarian function by regulating the NCOA4–FTH pathway, suggesting a potential therapeutic target for PCOS.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168108"},"PeriodicalIF":4.2,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524847","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 : 2025-11-11DOI: 10.1016/j.bbadis.2025.168107
Carmen Yap , Myrthe E. Hoogeland , Siyu Li , Iris Bakker , Ela Yalcin , Roelof Ottenhoff , Maria P. Clemente-Olivo , Sander Kooijman , Yousef Morcos , Gerhard Sengle , Vivian de Waard
Background and aims
Marfan syndrome (MFS) is a systemic disorder, caused by different pathogenic variants in the fibrillin-1 gene (FBN1). Interestingly, patients with MFS are often characterized with an asthenic body type, most likely associated with systemic metabolic alterations. We evaluate the effects of a high-fat diet (HFD) on aortic pathology and metabolism in a mouse model of MFS.
Methods and results
Male Fbn1C1041G/+ MFS mice and wild-type littermates were fed a chow or a HFD for 13 weeks. Compared to chow, HFD-fed mice show increased body weight and white adipose tissue, developed glucose intolerance and increased the use of fat as a fuel source indicated by lower respiratory exchange ratio, independent of genotype. MFS mice showed an increased heart tissue weight, increase in aortic root diameter, and higher number of elastin breaks in the aorta compared to wild-type mice when fed a chow diet. The aortic diameter did not further increase upon HFD feeding in MFS mice, while HFD did promote aortic dilation of the ascending aorta of wild-type mice. In most examined tissues, the mitochondrial gene expression profile is altered in MFS mice on a chow diet. Especially Sirt1 was reduced in all tissues, with HFD normalizing the MFS profile towards a wild-type profile. The latter may contribute to the observed increase in energy expenditure upon HFD in MFS mice.
Conclusion
In conclusion, Fbn1C1041G/+ MFS aortic pathology is not aggravated by the HFD, most likely due to the increase of mitochondrial gene expression upon HFD in MFS mice.
{"title":"High-fat diet does not exacerbate aortic pathology and enhances metabolic function in Marfan syndrome Fbn1C1041G/+ mice","authors":"Carmen Yap , Myrthe E. Hoogeland , Siyu Li , Iris Bakker , Ela Yalcin , Roelof Ottenhoff , Maria P. Clemente-Olivo , Sander Kooijman , Yousef Morcos , Gerhard Sengle , Vivian de Waard","doi":"10.1016/j.bbadis.2025.168107","DOIUrl":"10.1016/j.bbadis.2025.168107","url":null,"abstract":"<div><h3>Background and aims</h3><div>Marfan syndrome (MFS) is a systemic disorder, caused by different pathogenic variants in the fibrillin-1 gene (<em>FBN1</em>). Interestingly, patients with MFS are often characterized with an asthenic body type, most likely associated with systemic metabolic alterations. We evaluate the effects of a high-fat diet (HFD) on aortic pathology and metabolism in a mouse model of MFS.</div></div><div><h3>Methods and results</h3><div>Male <em>Fbn1</em><sup>C1041G/+</sup> MFS mice and wild-type littermates were fed a chow or a HFD for 13 weeks. Compared to chow, HFD-fed mice show increased body weight and white adipose tissue, developed glucose intolerance and increased the use of fat as a fuel source indicated by lower respiratory exchange ratio, independent of genotype. MFS mice showed an increased heart tissue weight, increase in aortic root diameter, and higher number of elastin breaks in the aorta compared to wild-type mice when fed a chow diet. The aortic diameter did not further increase upon HFD feeding in MFS mice, while HFD did promote aortic dilation of the ascending aorta of wild-type mice. In most examined tissues, the mitochondrial gene expression profile is altered in MFS mice on a chow diet. Especially <em>Sirt1</em> was reduced in all tissues, with HFD normalizing the MFS profile towards a wild-type profile. The latter may contribute to the observed increase in energy expenditure upon HFD in MFS mice.</div></div><div><h3>Conclusion</h3><div>In conclusion, <em>Fbn1</em><sup>C1041G/+</sup> MFS aortic pathology is not aggravated by the HFD, most likely due to the increase of mitochondrial gene expression upon HFD in MFS mice.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168107"},"PeriodicalIF":4.2,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515133","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 : 2025-11-10DOI: 10.1016/j.bbadis.2025.168105
Congcong Geng , Junling Zhen , Na Zhu , Fangjian Wang , Rui Ji , Lei Sun , Huizhen Du , Shujun Yan , Ziyuan Zhong , Yufei Zang , Qian Wang
Targeted therapy, as an effective therapeutic strategy for the treatment of colorectal cancer (CRC), is still limited by its applicability to specific patient populations and drug resistance. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying the development of CRC and identify novel targeted biomarkers. CACNA2D3 encodes the α2δ3 subunit of calcium (Ca2+) channels, and recent studies have consistently demonstrated its potential as a tumor suppressor. MicroRNAs (miRNAs) act by binding to the 3'-UTR of mRNAs to inhibit the function of target genes. Currently, the underlying mechanisms of CACNA2D3 and its upstream miRNAs in CRC remain elusive. Our study revealed that CACNA2D3, which is expressed at low levels in CRC, inhibits CRC cell proliferation and promotes apoptosis by up-regulating intracellular Ca2+ and ROS levels and activating the mitochondrial apoptotic pathway. miR-27a-3p, whose expression level is significantly upregulated in CRC, is an upstream miRNA of CACNA2D3, and promote the progression of CRC by negatively regulating CACNA2D3.By exploring the mechanism of action of CACNA2D3 in colorectal cancer and identifying potential upstream microRNAs, we aim to provide a new strategy for targeted therapy for CRC.
{"title":"miR-27a-3p targets CACNA2D3 to promote colorectal cancer progression via the Ca2+/ROS/mitochondrial apoptotic pathway","authors":"Congcong Geng , Junling Zhen , Na Zhu , Fangjian Wang , Rui Ji , Lei Sun , Huizhen Du , Shujun Yan , Ziyuan Zhong , Yufei Zang , Qian Wang","doi":"10.1016/j.bbadis.2025.168105","DOIUrl":"10.1016/j.bbadis.2025.168105","url":null,"abstract":"<div><div>Targeted therapy, as an effective therapeutic strategy for the treatment of colorectal cancer (CRC), is still limited by its applicability to specific patient populations and drug resistance. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying the development of CRC and identify novel targeted biomarkers. CACNA2D3 encodes the α2δ3 subunit of calcium (Ca<sup>2+</sup>) channels, and recent studies have consistently demonstrated its potential as a tumor suppressor. MicroRNAs (miRNAs) act by binding to the 3'-UTR of mRNAs to inhibit the function of target genes. Currently, the underlying mechanisms of CACNA2D3 and its upstream miRNAs in CRC remain elusive. Our study revealed that CACNA2D3, which is expressed at low levels in CRC, inhibits CRC cell proliferation and promotes apoptosis by up-regulating intracellular Ca<sup>2+</sup> and ROS levels and activating the mitochondrial apoptotic pathway. miR-27a-3p, whose expression level is significantly upregulated in CRC, is an upstream miRNA of CACNA2D3, and promote the progression of CRC by negatively regulating CACNA2D3.By exploring the mechanism of action of CACNA2D3 in colorectal cancer and identifying potential upstream microRNAs, we aim to provide a new strategy for targeted therapy for CRC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168105"},"PeriodicalIF":4.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497690","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":"2025-11-07","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 : 2025-11-05DOI: 10.1016/j.bbadis.2025.168103
Arveen Shokravi , Yuchen Luo , Simon W. Rabkin
Background
The objectives of this systematic review and meta-analysis were to (i) evaluate the relationship between circulating levels choline and its metabolites, phosphatidylcholine (PC), trimethylamine N-oxide (TMAO), betaine, and dimethylglycine (DMG) with heart failure (HF) development and its adverse clinical outcomes (ii) explore potential mechanisms that link them to HF.
Methods
A systematic search of MEDLINE, EMBASE, and PubMed was conducted.
Results
Nine prospective cohort studies (n = 267,569) were analysed. Elevated choline and PC were significantly associated with an increased incidence of HF respectively HR 1.33 (95 % CI 1.07–1.66, p = 0.0107) and HR 1.25 (95 % CI 1.16–1.34, p < 0.0001). In established HF, elevated betaine levels were significantly associated with a composite of adverse clinical outcomes (HR 1.15, 95 % CI 1.02–1.30, p = 0.0206). The molecular mechanisms linking choline and PC to HF include the hydrolysis of PC into lysophosphatidylcholine which can produce inflammation and cardiomyocyte apoptosis. Several metabolites and pathways are intriguing therapeutic targets, including lysophosphatidylcholine acyltransferase 1, phospholipase A2, choline trimethylamine lyase, and the phosphatidylethanolamine N-methyltransferase pathway.
Conclusions
Choline metabolites are implicated in HF development and progression. Understanding the mechanism whereby choline metabolism leads to HF may lead to novel therapeutic targets for HF management and prevention.
背景：目的是(i)评估循环胆碱及其代谢物、磷脂酰胆碱（PC）、三甲胺n -氧化物（TMAO）、甜菜碱和二甲基甘氨酸（DMG）与心力衰竭（HF）发展及其不良临床结局之间的关系（ii）探索它们与HF相关的潜在机制。方法：系统检索MEDLINE、EMBASE和PubMed。结果：对9项前瞻性队列研究（n = 267,569）进行了分析。升高的胆碱和PC分别与HF发生率增加显著相关，HR为1.33（95 % CI 1.07-1.66, p = 0.0107）和HR为1.25（95 % CI 1.16-1.34, p ）。了解胆碱代谢导致心衰的机制可能会导致新的心衰治疗靶点。
{"title":"Unraveling the choline pathway in heart failure risk and outcomes: A systematic review and meta-analysis","authors":"Arveen Shokravi , Yuchen Luo , Simon W. Rabkin","doi":"10.1016/j.bbadis.2025.168103","DOIUrl":"10.1016/j.bbadis.2025.168103","url":null,"abstract":"<div><h3>Background</h3><div>The objectives of this systematic review and meta-analysis were to (i) evaluate the relationship between circulating levels choline and its metabolites, phosphatidylcholine (PC), trimethylamine N-oxide (TMAO), betaine, and dimethylglycine (DMG) with heart failure (HF) development and its adverse clinical outcomes (ii) explore potential mechanisms that link them to HF.</div></div><div><h3>Methods</h3><div>A systematic search of MEDLINE, EMBASE, and PubMed was conducted.</div></div><div><h3>Results</h3><div>Nine prospective cohort studies (<em>n</em> = 267,569) were analysed. Elevated choline and PC were significantly associated with an increased incidence of HF respectively HR 1.33 (95 % CI 1.07–1.66, <em>p</em> = 0.0107) and HR 1.25 (95 % CI 1.16–1.34, <em>p</em> < 0.0001). In established HF, elevated betaine levels were significantly associated with a composite of adverse clinical outcomes (HR 1.15, 95 % CI 1.02–1.30, <em>p</em> = 0.0206). The molecular mechanisms linking choline and PC to HF include the hydrolysis of PC into lysophosphatidylcholine which can produce inflammation and cardiomyocyte apoptosis. Several metabolites and pathways are intriguing therapeutic targets, including lysophosphatidylcholine acyltransferase 1, phospholipase A2, choline trimethylamine lyase, and the phosphatidylethanolamine <em>N</em>-methyltransferase pathway.</div></div><div><h3>Conclusions</h3><div>Choline metabolites are implicated in HF development and progression. Understanding the mechanism whereby choline metabolism leads to HF may lead to novel therapeutic targets for HF management and prevention.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168103"},"PeriodicalIF":4.2,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472607","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}
Type 2 diabetes mellitus (T2DM) and hyperuricemia (HUA) are increasingly recognized as interrelated metabolic disorders with shared pathogenic pathways and overlapping complications. Recent epidemiological evidence underscores a growing prevalence of their coexistence, particularly among obese and aging populations. Emerging mechanistic studies reveal a bidirectional relationship: elevated uric acid impairs insulin sensitivity and β-cell function via activation of oxidative stress, inflammation, and urate transporter dysregulation, while insulin resistance reduces renal urate excretion, forming a vicious metabolic cycle.
This review comprehensively summarizes the molecular and clinical interplay between T2DM and HUA, with a focus on oxidative stress signaling, RAAS activation, microbiota-derived metabolites, and gene–environment interactions (e.g., SLC2A9 variants). We highlight the therapeutic implications of glucose-lowering agents with urate-modulating properties, such as SGLT2 inhibitors and metformin, and assess the dual metabolic effects of uric acid–lowering agents. Furthermore, the potential of natural compounds—such as polyphenols, flavonoids, and probiotics—is discussed for their multi-target actions on inflammation, insulin signaling, and uric acid metabolism. In addition, recent advances in predictive modeling, microbiota modulation, and precision interventions offer novel avenues for integrated disease management. The integration of pharmacotherapy, lifestyle interventions, and digital health tools may facilitate personalized strategies for this dual metabolic burden. Future research should focus on elucidating causality, refining early diagnostic biomarkers, and developing targeted interventions for comprehensive metabolic control in patients with coexisting T2DM and HUA.
{"title":"Revisiting the metabolic crosstalk between type 2 diabetes and hyperuricemia: Pathophysiological insights and therapeutic perspectives","authors":"Xiuqiang Xia , Hongyu Niu , Changsong Xu , Xinghao Liu , Guoying Zhang , Jianya Ling","doi":"10.1016/j.bbadis.2025.168102","DOIUrl":"10.1016/j.bbadis.2025.168102","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) and hyperuricemia (HUA) are increasingly recognized as interrelated metabolic disorders with shared pathogenic pathways and overlapping complications. Recent epidemiological evidence underscores a growing prevalence of their coexistence, particularly among obese and aging populations. Emerging mechanistic studies reveal a bidirectional relationship: elevated uric acid impairs insulin sensitivity and β-cell function via activation of oxidative stress, inflammation, and urate transporter dysregulation, while insulin resistance reduces renal urate excretion, forming a vicious metabolic cycle.</div><div>This review comprehensively summarizes the molecular and clinical interplay between T2DM and HUA, with a focus on oxidative stress signaling, RAAS activation, microbiota-derived metabolites, and gene–environment interactions (e.g., <em>SLC2A9</em> variants). We highlight the therapeutic implications of glucose-lowering agents with urate-modulating properties, such as <em>SGLT2</em> inhibitors and metformin, and assess the dual metabolic effects of uric acid–lowering agents. Furthermore, the potential of natural compounds—such as polyphenols, flavonoids, and probiotics—is discussed for their multi-target actions on inflammation, insulin signaling, and uric acid metabolism. In addition, recent advances in predictive modeling, microbiota modulation, and precision interventions offer novel avenues for integrated disease management. The integration of pharmacotherapy, lifestyle interventions, and digital health tools may facilitate personalized strategies for this dual metabolic burden. Future research should focus on elucidating causality, refining early diagnostic biomarkers, and developing targeted interventions for comprehensive metabolic control in patients with coexisting T2DM and HUA.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168102"},"PeriodicalIF":4.2,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460799","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 : 2025-11-03DOI: 10.1016/j.bbadis.2025.168094
Yingjuan Wu , Yi Liu , Lina Shan , Xin Li , Bingyu Wu , Lixuan Guo
Pulmonary hypertension (PH) is a lethal vascular disorder characterized by hypoxia-driven vascular remodeling, yet the molecular mechanisms underlying endothelial dysfunction remain poorly understood. Here, we identify peroxiredoxin-1 (PRDX1) as a critical mediator of PH pathogenesis through redox-independent regulation of mitochondrial dynamics. Hypoxia upregulated PRDX1 expression in human pulmonary artery endothelial cells (HPAECs) via HIF1α-dependent transcriptional activation, as demonstrated by chromatin immunoprecipitation and promoter-luciferase assays. PRDX1 silencing attenuated hypoxia-induced HPAEC proliferation and apoptosis resistance, while its overexpression mimicked hypoxic effects independently of its antioxidant activity. Mechanistically, PRDX1 directly interacted with Dynamin-related protein 1 (DRP1) and facilitated sentrin-specific protease 3 (SENP3) binding, suppressing DRP1 SUMO2/3 conjugation to promote mitochondrial fission. In vivo, endothelial-specific PRDX1 knockdown in a hypoxia/SU5416(SuHx)-induced PH rat model significantly reduced right ventricular systolic pressure, vascular wall thickening, and endothelial hyperproliferation, while improving exercise tolerance. These findings reveal a novel HIF1α-PRDX1-DRP1 axis driving mitochondrial fragmentation and vascular remodeling in PH, positioning PRDX1 as a promising therapeutic target for halting disease progression.
{"title":"HIF1α/PRDX1 axis drives pulmonary vascular remodeling through DRP1 DeSUMOylation and mitochondrial fragmentation","authors":"Yingjuan Wu , Yi Liu , Lina Shan , Xin Li , Bingyu Wu , Lixuan Guo","doi":"10.1016/j.bbadis.2025.168094","DOIUrl":"10.1016/j.bbadis.2025.168094","url":null,"abstract":"<div><div>Pulmonary hypertension (PH) is a lethal vascular disorder characterized by hypoxia-driven vascular remodeling, yet the molecular mechanisms underlying endothelial dysfunction remain poorly understood. Here, we identify peroxiredoxin-1 (PRDX1) as a critical mediator of PH pathogenesis through redox-independent regulation of mitochondrial dynamics. Hypoxia upregulated PRDX1 expression in human pulmonary artery endothelial cells (HPAECs) via HIF1α-dependent transcriptional activation, as demonstrated by chromatin immunoprecipitation and promoter-luciferase assays. PRDX1 silencing attenuated hypoxia-induced HPAEC proliferation and apoptosis resistance, while its overexpression mimicked hypoxic effects independently of its antioxidant activity. Mechanistically, PRDX1 directly interacted with Dynamin-related protein 1 (DRP1) and facilitated sentrin-specific protease 3 (SENP3) binding, suppressing DRP1 SUMO2/3 conjugation to promote mitochondrial fission. In vivo, endothelial-specific PRDX1 knockdown in a hypoxia/SU5416(SuHx)-induced PH rat model significantly reduced right ventricular systolic pressure, vascular wall thickening, and endothelial hyperproliferation, while improving exercise tolerance. These findings reveal a novel HIF1α-PRDX1-DRP1 axis driving mitochondrial fragmentation and vascular remodeling in PH, positioning PRDX1 as a promising therapeutic target for halting disease progression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168094"},"PeriodicalIF":4.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454423","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}
Mitochondrial dysfunction and immune dysregulation contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study systematically identifies mitochondrial-related core regulatory genes and elucidates their potential associations with immunological features in IPF. Two independent IPF cohorts (GSE110147 and GSE32537) were integrated as a training set, followed by a differential expression analysis to identify IPF-specific gene signatures. Weighted gene co-expression network analysis (WGCNA) was used to detect disease-associated modules, which were cross-screened against mitochondrial gene databases. A multi-model framework incorporating Least Absolute Shrinkage and Selection Operator (LASSO) regression, Random Forest (RF), and Support Vector Machine Recursive Feature Elimination (SVM-RFE) identified core candidate genes. An independent dataset (GSE24206) was used for external validation, with diagnostic efficacy evaluated using receiver operating characteristic (ROC) curve analysis. Expression patterns of key genes were validated in bleomycin-induced BEAS-2B cells. Immune cell infiltration was quantified using the CIBERSORT deconvolution algorithm. Our results showed WGCNA, LASSO regression, RF, and SVM-RFE algorithms identified three key genes, ABCD2, CROT, and CYP24A1, which were significantly upregulated in the lung tissues of patients with IPF. Their ROC curves demonstrated excellent diagnostic performance. These findings were confirmed by the results from bleomycin-induced BEAS-2B cells. Functional experiments showed that CROT silencing reduced α-smooth muscle actin expression, increased E-cadherin levels in bleomycin-induced BEAS-2B cells. Our results indicate that CROT is associated with EMT and immune-cell alterations in IPF. Thus, CROT may serve as a potential therapeutic target for regulating the immune response disorder in IPF.
{"title":"Integrated bioinformatics and machine learning analysis identify CROT as a regulator of immunological features in idiopathic pulmonary fibrosis","authors":"Tingting Song, Mengfan Bu, Qianling Song, Beibei Zhan, Wenning Liu, Mengxin Hu, Guangcui Xu, Zijiang Yang, Keda Zhao, Yichun Bai, Sanqiao Yao, Yingzheng Zhao","doi":"10.1016/j.bbadis.2025.168100","DOIUrl":"10.1016/j.bbadis.2025.168100","url":null,"abstract":"<div><div>Mitochondrial dysfunction and immune dysregulation contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study systematically identifies mitochondrial-related core regulatory genes and elucidates their potential associations with immunological features in IPF. Two independent IPF cohorts (GSE110147 and GSE32537) were integrated as a training set, followed by a differential expression analysis to identify IPF-specific gene signatures. Weighted gene co-expression network analysis (WGCNA) was used to detect disease-associated modules, which were cross-screened against mitochondrial gene databases. A multi-model framework incorporating Least Absolute Shrinkage and Selection Operator (LASSO) regression, Random Forest (RF), and Support Vector Machine Recursive Feature Elimination (SVM-RFE) identified core candidate genes. An independent dataset (GSE24206) was used for external validation, with diagnostic efficacy evaluated using receiver operating characteristic (ROC) curve analysis. Expression patterns of key genes were validated in bleomycin-induced BEAS-2B cells. Immune cell infiltration was quantified using the CIBERSORT deconvolution algorithm. Our results showed WGCNA, LASSO regression, RF, and SVM-RFE algorithms identified three key genes, <em>ABCD2</em>, <em>CROT</em>, and <em>CYP24A1</em>, which were significantly upregulated in the lung tissues of patients with IPF. Their ROC curves demonstrated excellent diagnostic performance. These findings were confirmed by the results from bleomycin-induced BEAS-2B cells. Functional experiments showed that <em>CROT</em> silencing reduced α-smooth muscle actin expression, increased <em>E-cadherin</em> levels in bleomycin-induced BEAS-2B cells. Our results indicate that <em>CROT</em> is associated with EMT and immune-cell alterations in IPF. Thus, <em>CROT</em> may serve as a potential therapeutic target for regulating the immune response disorder in IPF.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168100"},"PeriodicalIF":4.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454454","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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