Cell and Bioscience最新文献

{"title":"Canonical and non-canonical functions of the non-coding RNA component (TERC) of telomerase complex.","authors":"Chongwen Cao, Weiyi Gong, Yuanlong Shuai, Sara Rasouli, Qianyun Ge, Anam Khan, Aleksandra Dakic, Nagireddy Putluri, Gennady Shvets, Yun-Ling Zheng, Danyal Daneshdoust, Rani Mahyoob, Jenny Li, Xuefeng Liu","doi":"10.1186/s13578-025-01367-0","DOIUrl":"10.1186/s13578-025-01367-0","url":null,"abstract":"<p><p>The telomerase complex consists of a protein component (TERT), which has reverse transcriptase activity, and an RNA component (TERC), which serves as a template for telomere synthesis. Evidence is rapidly accumulating regarding the non-canonical functions of these components in both normal or diseased cells. An oligonucleotide-based drug, the first telomerase inhibitor, secured FDA approval in June 2024. We recently summarized the non-canonical functions of TERT in viral infections and cancer. In this review, we expand on these non-canonical functions of TERC beyond telomere maintenance. Specifically, we explore TERC's roles in cellular aging and senescence, immune regulation, genetic diseases, human cancer, as well as involvement in viral infections and host interactions. Finally, we discuss a transcription product of telomere repeats, TERRA, and explore strategies for targeting TERC as a therapeutic approach.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"30"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537985","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":"Multiple functions of the ALT favorite helicase, BLM.","authors":"Shun Chang, Jiang Tan, Ren Bao, Yanduo Zhang, Jinkai Tong, Tongxin Jia, Jing Liu, Juhua Dan, Shuting Jia","doi":"10.1186/s13578-025-01372-3","DOIUrl":"10.1186/s13578-025-01372-3","url":null,"abstract":"<p><p>Eukaryotic somatic cells undergo continuous telomere shortening because of end-replication problems. Approximately 10%~15% of human cancers rely on alternative lengthening of telomeres (ALT) to overcome telomere shortening. ALT cells are characterized by persistent telomere DNA replication stress and rely on recombination-based DNA repair pathways for telomere elongation. The Bloom syndrome (BLM) helicase is a member of the RecQ family, which has been implicated as a key regulator of the ALT mechanism as it is required for either telomere length maintenance or telomere clustering in ALT-associated promyelocytic leukemia bodies (APBs). Here, we summarize recent evidence detailing the role of BLM in the activation and maintenance of ALT. We propose that the role of BLM-dependent recombination and its interacting proteins remains a crucial question for future research in dissecting the molecular mechanisms of ALT.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"31"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537988","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":"Altered synaptic homeostasis: a key factor in the pathophysiology of depression.","authors":"Bokai Wang, Teng He, Guofan Qiu, Chong Li, Song Xue, Yuanjia Zheng, Taiyi Wang, Yucen Xia, Lin Yao, Jinglan Yan, Yongjun Chen","doi":"10.1186/s13578-025-01369-y","DOIUrl":"10.1186/s13578-025-01369-y","url":null,"abstract":"<p><p>Depression, a widespread psychiatric disorder, is characterized by a diverse array of symptoms such as melancholic mood and anhedonia, imposing a significant burden on both society and individuals. Despite extensive research into the neurobiological foundations of depression, a complete understanding of its complex mechanisms is yet to be attained, and targeted therapeutic interventions remain under development. Synaptic homeostasis, a compensatory feedback mechanism, involves neurons adjusting synaptic strength by regulating pre- or postsynaptic processes. Recent advancements in depression research reveal a crucial association between the disorder and disruptions in synaptic homeostasis within neural regions and circuits pivotal for emotional and cognitive functions. This paper explores the mechanisms governing synaptic homeostasis in depression, focusing on the role of ion channels, the regulation of presynaptic neurotransmitter release, synaptic scaling processes, and essential signaling molecules. By mapping new pathways in the study of synaptic homeostasis as it pertains to depression, this research aims to provide valuable insights for identifying novel therapeutic targets for more effective antidepressant treatments.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"29"},"PeriodicalIF":6.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143505474","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":"The m6A revolution: transforming tumor immunity and enhancing immunotherapy outcomes.","authors":"Tongguo Shi, Huan Zhang, Yueqiu Chen","doi":"10.1186/s13578-025-01368-z","DOIUrl":"10.1186/s13578-025-01368-z","url":null,"abstract":"<p><p>N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in the development and progression of various diseases, including cancer, through its regulation of RNA degradation, stabilization, splicing, and cap-independent translation. Emerging evidence underscores the significant role of m6A modifications in both pro-tumorigenic and anti-tumorigenic immune responses. In this review, we provide a comprehensive overview of m6A modifications and examine the relationship between m6A regulators and cancer immune responses. Additionally, we summarize recent advances in understanding how m6A modifications influence tumor immune responses by directly modulating immune cells (e.g., dendritic cells, tumor-associated macrophages, and T cells) and indirectly affecting cancer cells via mechanisms such as cytokine and chemokine regulation, modulation of cell surface molecules, and metabolic reprogramming. Furthermore, we explore the potential synergistic effects of targeting m6A regulators in combination with immune checkpoint inhibitor (ICI) therapies. Together, this review consolidates current knowledge on the role of m6A-mediated regulation in tumor immunity, offering insights into how a deeper understanding of these modifications may identify patients who are most likely to benefit from immunotherapies.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"27"},"PeriodicalIF":6.1,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477228","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":"Enhanced exosome secretion regulated by microglial P2X7R in the medullary dorsal horn contributes to pulpitis-induced pain.","authors":"Jing Zhang, Zhuo Yu, Mingjun Wang, Xiaoning Kang, Xiaoke Wu, Fengjiao Yang, Lu Yang, Shukai Sun, Li-An Wu","doi":"10.1186/s13578-025-01363-4","DOIUrl":"10.1186/s13578-025-01363-4","url":null,"abstract":"<p><strong>Background: </strong>Pulpitis is a prevalent oral disease characterized by severe pain. The activation of microglia in the medullary dorsal horn (MDH) is reportedly essential for the central sensitization mechanism associated with pulpitis. The P2X7 receptor (P2X7R) on microglia can trigger the secretion of exosomes enriched with IL-1β, which is involved in inflammation. Thus, we hypothesized that the enhanced exosome secretion regulated by microglial P2X7R in the MDH contributes to pulpitis-induced pain.</p><p><strong>Methods: </strong>An experimental pulpitis model was established in male SD rats to observe pain behaviors. Immunofluorescence staining, western blotting and quantitative real-time PCR were used to analyze the expression of IL-1β and Rab27a, a key protein secreted by exosomes during nociceptive processes. The effects of the exosome inhibitor GW4869 and the P2X7R antagonist Brilliant Blue G (BBG) on microglial P2X7R, exosome secretion and inflammation in the pulpitis model were analyzed. In vitro, microglial cells were cultured to collect exosomes, and stimulation with lipopolysaccharide (LPS), oxidized ATP (oxATP) and GW4869 altered the secretion of exosomes containing IL-1β.</p><p><strong>Results: </strong>In the experimental pulpitis model, the microglial exosome secretion and inflammatory factor release in the MDH were both correlated with the extent of pulpitis-induced pain, with the highest expression occurring on the 7th day. GW4869 and BBG inhibited Rab27a and IL-1β expression, reducing pulpitis-induced pain. In addition, exosomes were successfully extracted by ultracentrifugation in vitro, wherein LPS treatment promoted exosome secretion but GW4869 had the opposite effects on the secretion of exosomes and the IL-1β. Moreover, P2X7R inhibition by oxATP diminished exosome secretion, leading to a reduction in inflammatory responses.</p><p><strong>Conclusion: </strong>This study highlights the regulatory role of microglial P2X7R in increased exosome secretion, indicating the potential utility of P2X7R as a promising target for pulpitis therapy. Our research highlights a new pulpitis mechanism in which exosomes enriched with IL-1β contribute to pulpitis-induced pain, suggesting the crucial roles of exosomes as pain biomarkers and harmful signaling molecules during pulpitis.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"28"},"PeriodicalIF":6.1,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11847359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477227","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":"Whole-genome bisulfite sequencing of cell-free DNA unveils age-dependent and ALS-associated methylation alterations.","authors":"Yulin Jin, Karen N Conneely, Wenjing Ma, Robert K Naviaux, Teepu Siddique, Emily G Allen, Sandra Guingrich, Robert M Pascuzzi, Peng Jin","doi":"10.1186/s13578-025-01366-1","DOIUrl":"10.1186/s13578-025-01366-1","url":null,"abstract":"<p><strong>Background: </strong>Cell-free DNA (cfDNA) in plasma carries epigenetic signatures specific to tissue or cell of origin. Aberrant methylation patterns in circulating cfDNA have emerged as valuable tools for noninvasive cancer detection, prenatal diagnostics, and organ transplant assessment. Such epigenetic changes also hold significant promise for the diagnosis of neurodegenerative diseases, which often progresses slowly and has a lengthy asymptomatic period. However, genome-wide cfDNA methylation changes in neurodegenerative diseases remain poorly understood.</p><p><strong>Results: </strong>We used whole-genome bisulfite sequencing (WGBS) to profile age-dependent and ALS-associated methylation signatures in cfDNA from 30 individuals, including young and middle-aged controls, as well as ALS patients with matched controls. We identified 5,223 age-related differentially methylated loci (DMLs) (FDR < 0.05), with 51.6% showing hypomethylation in older individuals. Our results significantly overlapped with age-associated CpGs identified in a large blood-based epigenome-wide association study (EWAS). Comparing ALS patients to controls, we detected 1,045 differentially methylated regions (DMRs) in gene bodies, promoters, and intergenic regions. Notably, these DMRs were linked to key ALS-associated pathways, including endocytosis and cell adhesion. Integration with spinal cord transcriptomics revealed that 31% of DMR-associated genes exhibited differential expression in ALS patients compared to controls, with over 20 genes significantly correlating with disease duration. Furthermore, comparison with published single-nucleus RNA sequencing (snRNA-Seq) data of ALS demonstrated that cfDNA methylation changes reflects cell-type-specific gene dysregulation in the brain of ALS patients, particularly in excitatory neurons and astrocytes. Deconvolution of cfDNA methylation profiles suggested altered proportions of immune and liver-derived cfDNA in ALS patients.</p><p><strong>Conclusions: </strong>cfDNA methylation is a powerful tool for assessing age-related changes and ALS-specific molecular dysregulation by revealing perturbed locus, genes, and the proportional contributions of different tissues/cells to the plasma. This technique holds promise for clinical application in biomarker discovery across a broad spectrum of neurodegenerative disorders.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"26"},"PeriodicalIF":6.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469703","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":"A translational perspective of the malignant hematopoietic proteoglycome.","authors":"Naomi Borghini, Mirca Lazzaretti, Paolo Lunghi, Giorgio Malpeli, Stefano Barbi, Roberto Perris","doi":"10.1186/s13578-025-01360-7","DOIUrl":"10.1186/s13578-025-01360-7","url":null,"abstract":"<p><p>Proteoglycans are an ample family of complex extracellular matrix/cell surface components known to impact on virtually all biological processes that take place during life of a human being, in its healthy and diseased conditions. They are consolidated multivalent regulators of the behaviour of normal and malignant hematopoietic cells because of being critical components of their membranes, because of their pivotal role as multifaceted factors of the hematopoietic niches and because of acting as pillars of the tumour microenvironment. Likewise, they act as promoters of the growth, spreading and therapeutic resistance of diseased hematopoietic cells, also by modulating intracellular processes through a dual utilization of core protein domains and their glycosaminoglycan side chains. The intricate pattern of expression of the myriads of proteoglycan isoforms generated by differential glycanations of the core proteins is differentiation- and cell activation-dependent and often associates with genomic aberrations and gene amplifications. Selected proteoglycans stand out as widely recognized, disease type-specific markers and as alluring but still unappreciated therapeutic targets. We therefore pose here a clinical-translational view on the hematopoietic proteoglycome to highlight its underestimated biological and pathological significance during normal and neoplastic hematopoiesis. We underscore the potential of several proteoglycans to be exploited as key markers for prognostication and therapeutic targeting of hematopoietic cancers.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"25"},"PeriodicalIF":6.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469702","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":"The lncRNA MIR181A1HG in extracellular vesicles derived from highly metastatic colorectal cancer cells promotes liver metastasis by remodeling the extracellular matrix and recruiting myeloid-derived suppressor cells.","authors":"Yichao Gu, Yushuai Mi, Yifan Cao, Kuan Yu, Zihao Zhang, Peng Lian, Dawei Li, Jing Qin, Senlin Zhao","doi":"10.1186/s13578-025-01365-2","DOIUrl":"10.1186/s13578-025-01365-2","url":null,"abstract":"<p><strong>Background: </strong>Colorectal liver metastasis (CRLM) is the main cause of death in colorectal cancer (CRC) patients worldwide. In the initial stage of metastasis, primary tumors provide the necessary conditions for metastasis by shaping the local microenvironment of the target organ, forming \"premetastatic niches\" (PMNs), and extracellular vesicles (EVs) play important roles in shaping PMNs. Therefore, investigating the EVs involved in the regulation of PMNs and their mechanism is highly valuable for the further understanding of CRLM.</p><p><strong>Methods: </strong>Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify the roles of MIR181A1HG in EVs in CRLM. RNA pull-down and dual-luciferase reporter assays were used to clarify the mechanism by which MIR181A1HG in EVs regulated the crosstalk between CRC cells and hepatic stellate cells (HSCs).</p><p><strong>Results: </strong>We demonstrated that the lncRNA MIR181A1HG was progressively upregulated in tissues, serum EVs from healthy normal controls to CRC and paired liver metastatic groups. Additionally, we verified that HNRNPA2B1 mediated the packaging of MIR181A1HG into CRC cell-derived EVs, which in turn functioned as a ceRNA by sponging miR373-3p to activate HSCs via the TGFβRII/Smad2/3 signaling pathway. Furthermore, activated HSCs could secrete the chemokine CXCL12 to promote CRLM by remodeling the extracellular matrix and recruiting myeloid-derived suppressor cells in the liver, which resulted in liver metastasis.</p><p><strong>Conclusions: </strong>MIR181A1HG in EVs from highly metastatic CRC cells promoted CRLM by activating HSCs to form PMNs in the liver, which contributes to the further understanding of the mechanism of CRLM and provides potential predictive markers for CRLM.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"23"},"PeriodicalIF":6.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460212","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":"KAT8 catalyzes the acetylation of SEPP1 at lysine 247/249 and modulates the activity of CD8⁺ T cells via LRP8 to promote anti-tumor immunity in pancreatic cancer.","authors":"Zhongfei Zhu, Gang Nie, Xiaobo Peng, Xianbao Zhan, Dan Ding","doi":"10.1186/s13578-025-01356-3","DOIUrl":"10.1186/s13578-025-01356-3","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer (PC) remains one of the most lethal malignancies with unfavorable prognosis globally. Bioinformatics analysis predicted that SEPP1 was low expressed in PC and related to tumor immune microenvironment, but its biological function was still unclear.</p><p><strong>Methods: </strong>PC xenograft and liver metastasis mouse models, as well as PC cell-MDSCs co-culture system, were established for in vivo and in vitro studies, respectively. The expression and localization of key molecules were detected by qRT-PCR, western blot, immunohistochemistry and immunofluorescence. Flow cytometry was employed to assess the abundance of immune cells and cell apoptosis. The interactions among KAT8, SEPP1 and LRP8 were detected by co-IP. Cell viability, migration and invasion were monitored by CCK-8 and transwell assays.</p><p><strong>Results: </strong>SEPP1 was downregulated in pancreatic tumors, and it was positively correlated with the abundance of CD8⁺ T cells. In vivo overexpression of SEPP1 impaired PC tumor growth and liver metastasis via modulating the abundance of CD8⁺ T cell and MDSCs. KAT8 upregulated SEPP1 transcription and protein level via catalyzing the acetylation at K247/249 on SEPP1, and SEPP1 impaired MDSCs survival via its receptor LRP8, thus regulating CD8⁺ T cell-mediated immune responses in PC. In vivo studies further revealed that SEPP1 recombinant protein enhanced the efficacy of anti-PD-1 therapy in PC xenograft mouse model.</p><p><strong>Conclusion: </strong>KAT8 catalyzed the acetylation of SEPP1 at K247/249 and modulated the activity of CD8⁺ T cells via LRP8 to promote anti-tumor immunity in PC.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"24"},"PeriodicalIF":6.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460210","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":"Enpp1 ameliorates MAFLD by regulating hepatocyte lipid metabolism through the AMPK/PPARα signaling pathway.","authors":"Xiaohui Liu, Shuai Chen, Xing Liu, Xianxian Wu, Xiaoliang Jiang, Yuhan Li, Zhiwei Yang","doi":"10.1186/s13578-025-01364-3","DOIUrl":"10.1186/s13578-025-01364-3","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the leading chronic liver disease globally, and there are no approved pharmacotherapies to treat this disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) has been found to be related to insulin resistance and lipid accumulation. However, the role and mechanism of Enpp1 in the development of MAFLD remain unknown.</p><p><strong>Results: </strong>Here we discovered that Enpp1 is lowly expressed in the liver of MAFLD patients by clinical investigation. Knocking out Enpp1 in the liver of mice aggravated obesity, insulin resistance and hepatic steatosis, and these effects were reversed by liver-specific Enpp1 overexpression. Through transcriptomic data mining and experimental validation, we demonstrated that Enpp1 deficiency inhibited the expression of AMPK (energy receptor) and PPARα (nuclear transcription factor for lipid metabolism), thereby promoting the transcription of lipid synthesis factors and mediating the progression of MAFLD. Mechanistically, Enpp1 enhanced the activity of AMPK by increasing the AMP-to-ATP ratio, which in turn raised PPARα levels and promoted the transcription of its downstream lipid metabolism factors. Pharmacological inhibition of AMPK activity abolished the promoting effect of Enpp1 on PPARα protein expression.</p><p><strong>Conclusions: </strong>This study indicate that Enpp1 can effectively ameliorate MAFLD through effects on AMPK/PPARα signaling pathway-mediated lipid metabolism, revealing the significance of Enpp1 as a promising therapeutic target against MAFLD.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"22"},"PeriodicalIF":6.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460208","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}