Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"The interplay between lipid droplets and Parkinson's disease","authors":"Xin-ru Zhao ,&nbsp;Ying-ying Gu ,&nbsp;Jia-yi Wang ,&nbsp;Ying Yi ,&nbsp;Yan-qiu Zhang ,&nbsp;Qian-hang Shao ,&nbsp;Ming-xuan Liu ,&nbsp;Xiao-ling Zhang","doi":"10.1016/j.bbadis.2025.167953","DOIUrl":"10.1016/j.bbadis.2025.167953","url":null,"abstract":"<div><div>Lipid droplets (LDs), also known as lipid bodies, are dynamic intracellular organelles that are rich in lipids. They serve critical functions in metabolic regulation, membrane dynamics, and cellular signaling pathways. LD homeostasis plays a key role in neurotransmission, receptor activation, and neural development. Intracellular LD accumulation contributes to lipotoxicity and precedes neurodegeneration such as Parkinson's disease (PD). While recent studies have advanced our knowledge regarding how LD accumulation influences PD progression, several fundamental aspects of LD biology remain unclear. This review explores key mechanisms of LD buildup in PD pathogenesis. First, we discuss the formation and physiological roles of LD, followed by an analysis of how impaired LD generation contributes to PD development. Second, we analyze the causal relationship between LD formation and degradation. Lastly, we evaluate the therapeutic potential of LDs as diagnostic biomarkers and molecular targets for innovative neuroprotective and anti-inflammatory strategies. Thus, advancing the mechanistic understanding of LD biology can provide key insights into PD pathogenesis, facilitating the design of targeted therapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167953"},"PeriodicalIF":4.2,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295496","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":"Airway fibroblasts drive IL-4-mediated Th2 polarization in airway allergy: Mechanisms and therapeutic targeting","authors":"Lihua Mo ,&nbsp;Le Liu ,&nbsp;Jinbiao Xie ,&nbsp;Jinna Yang ,&nbsp;Gaohui Wu ,&nbsp;Qinmiao Huang ,&nbsp;Pingchang Yang ,&nbsp;Xiangqian Luo","doi":"10.1016/j.bbadis.2025.167951","DOIUrl":"10.1016/j.bbadis.2025.167951","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>Airway fibroblasts in allergic asthma (AA) mice demonstrated a 2.3-fold increase in IL-4+ cell proportion (p &lt; 0.01), indicating their dominant role in driving Th2 inflammation compared to CD4+ T cells (24.7 % contribution, p &lt; 0.001).</div></span></li><li><span>•</span><span><div>Fibroblasts upregulated activation markers CD80/CD83/CD86 (p &lt; 0.0001), which correlated with enhanced IL-4-dependent Th2 polarization (30.01 % Teffs vs. 8.89 % with naive fibroblasts, p &lt; 0.0001), suggesting their capacity to amplify allergic responses.</div></span></li><li><span>•</span><span><div>Targeted FbNP therapy reduced pathological fibroblast frequency by 24.6 % and systemic IL-4 levels by 48.83 %, accompanied by significant suppression of Th2 cytokines (IL-5: 46.88 %; IL-13: 50.84 %, all p &lt; 0.001), demonstrating dual anti-inflammatory and immunoregulatory effects.</div></span></li><li><span>•</span><span><div>Clinically, FbNP alleviated asthma symptoms (52–65 % reduction in airway resistance) and improved airway hyperresponsiveness (AHR, 41 % correction, p &lt; 0.01), with sustained therapeutic efficacy for 14 days and no detectable toxicity.</div></span></li></ul></div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167951"},"PeriodicalIF":4.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287525","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":"Small extracellular vesicles from HO-1 modified BMMSCs alleviate steatotic liver grafts ischemia-reperfusion injury by delivering PDIA4 to promote reparative macrophage polarization","authors":"Huaiwen Zuo ,&nbsp;Yilin Pi ,&nbsp;Yuxin Wang ,&nbsp;Weiping Zheng ,&nbsp;Xinru Zhang ,&nbsp;Huiyuan Zhou ,&nbsp;Hongli Song","doi":"10.1016/j.bbadis.2025.167947","DOIUrl":"10.1016/j.bbadis.2025.167947","url":null,"abstract":"<div><div>Utilizing steatotic liver donors presents a viable strategy to mitigate the donor shortage in liver transplantation. However, severe steatosis increases the susceptibility of livers to ischemia-reperfusion injury (IRI) during transplantation, and regulating hepatic macrophage polarization can suppress liver inflammation and alleviate IRI. This study investigates the effects of small extracellular vesicles (sEVs) from heme oxygenase-1 (HO-1) modified bone marrow mesenchymal stem cells (BMMSCs), termed HM-sEVs, on IRI and macrophage polarization in steatotic liver grafts. We found that HM-sEVs significantly alleviated steatotic liver grafts IRI compared to sEVs from BMMSCs (M-sEVs). Further experiments have demonstrated that HM-sEVs can be internalized by macrophages and possess a greater capacity to promote reparative macrophage polarization and inhibit inflammatory responses, compared to M-sEVs. Mechanistically, protein disulfide-isomerase A4 (PDIA4) was found to be highly enriched in HM-sEVs. HM-sEVs can deliver PDIA4 to macrophages, activating the PDIA4/HSP90/MYC axis. This activation inhibits MYC ubiquitination and degradation, thereby promoting reparative macrophage polarization. In summary, our results indicated HM-sEVs can promote hepatic reparative macrophage polarization by activating the PDIA4/HSP90/MYC axis, providing a theoretical foundation for the application of HM-sEVs in alleviating steatotic liver grafts IRI and mitigating donor liver shortages.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167947"},"PeriodicalIF":4.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144242232","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":"Targeting Ca2+-activated K+ channels in glioma","authors":"Yuequ Zhang ,&nbsp;Hennrique Taborda Ribas ,&nbsp;Sheila M.B. Winnischofer ,&nbsp;Martina Schmidt ,&nbsp;Marina Trombetta-Lima ,&nbsp;Amalia M. Dolga","doi":"10.1016/j.bbadis.2025.167950","DOIUrl":"10.1016/j.bbadis.2025.167950","url":null,"abstract":"<div><div>Glioma affects millions of people worldwide and there is a lack of effective therapies. Glioblastoma multiforme (GBM) is the most common and deadliest form of primary brain tumor in adults. Emerging evidence indicated that targeting ion channels may be a promising therapeutic approach for GBM. Altered expression and activity of the Ca²⁺- activated K⁺ (K_Ca) channels have been reported in GBM patients. Generally, large-conductance K_Ca (BK_Ca) channels and intermediate-conductance K_Ca (IK_Ca or SK4) channels are highly expressed in glioma samples compared to healthy control brain tissue. Analyzing TCGA database, the expression of <em>KCNMB1</em> (encoding the BK_Ca channel protein) and <em>KCNN4</em> (encoding the K_Ca3.1/IK_Ca protein) genes was upregulated, while <em>KCNN1</em> (encoding the K_Ca2.1 protein) gene expression was downregulated in GBM patients grade IV compared to GBM patients grade I or II. The gene expression and activity of K_Ca channels may contribute to survival outcomes, by regulating cellular processes like cell proliferation and migration. Importantly, modulation of the activity of K_Ca channels reduced the proliferation and migration of GBM cells and suppressed glioma progression both in vivo and in vitro cell models for GBM. Herein, we aim to review how modulation of the activity of K_Ca channels impacts tumor development in terms of proliferation, cell death, invasion, metabolism and immune system in GBM.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167950"},"PeriodicalIF":4.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144242231","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":"Metabolic profile of human non-small cell lung cancer cells through combined 13C and 2H NMR","authors":"Ludgero C. Tavares ,&nbsp;Ricardo Amorim ,&nbsp;José Teixeira ,&nbsp;Paulo J. Oliveira ,&nbsp;Rui A. Carvalho","doi":"10.1016/j.bbadis.2025.167949","DOIUrl":"10.1016/j.bbadis.2025.167949","url":null,"abstract":"<div><div>The metabolic remodeling occurring in carcinogenesis cells is firmly established. However, to understand the connection between the cellular metabolic profile and carcinogenesis, an accurate measurement of metabolic fluxes is required. In order to quantify the fluxes in these metabolic pathways, stable isotope tracers and nuclear magnetic resonance (NMR) techniques were employed. For that purpose, two human non-small lung cancer cell lines (A549 and H1299) were used. For the quantification of carbon intermediary metabolism cells were grown in ¹³C labelled glucose while for <em>de novo</em> lipogenesis (DNL) assessment ²H₂O was supplemented to the culture media. To better understand and characterize cellular bioenergetics, mitochondrial membrane potential, oxygen consumption, and energy charge were also assessed. Finally, to establish a bridge between metabolic fluxes and cancer proliferation, substrate dependency studies were performed. Several metabolic inhibitors were also tested, targeting glycolysis, TCA cycle, pentose phosphate pathway (PPP) and transaminases.</div><div>Our results showed the occurrence of metabolic heterogeneity between the two non-small lung cancer cell lines: H1299 exhibited a relatively active TCA cycle, while A549 showed a more glycolytic phenotype. The overall mitochondrial bioenergetic parameters were in agreement with the metabolic profiles. The mitochondrial network was polarized and active in all cell lines, although the H1299 cell line exhibited higher basal oxygen consumption and spare respiratory capacity. Nonetheless, DNL rate did not differ in H1299 and A549 lung cancer cell lines. Additionally, α-ketoglutarate availability was proven a key determinant for H1299 non-small cell lung cancer cells survival and proliferation.</div><div>In conclusion, this work revealed that cells derived from a lymph node metastasis (H1299) have a more active TCA cycle and altered oxidative stress levels when compared to cells derived from a primary tumor (A549). In the process, we successfully implemented a new ²H enrichment method for DNL assessment for the first time in <em>in vitro</em> cancer research.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167949"},"PeriodicalIF":4.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251276","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":"Role of the CEACAM7-JAK2/STAT3-BST2 Axis in the migration of nasopharyngeal carcinoma cells","authors":"Ju-Pi Li ,&nbsp;Chiao-Wen Lin ,&nbsp;Yen-Ting Lu ,&nbsp;Cheng-Chen Huang ,&nbsp;Yu-Ting Ho ,&nbsp;Chung-Han Hsin ,&nbsp;Shun-Fa Yang","doi":"10.1016/j.bbadis.2025.167948","DOIUrl":"10.1016/j.bbadis.2025.167948","url":null,"abstract":"<div><h3>Objective</h3><div>Nasopharyngeal carcinoma (NPC) is a rare malignancy of the head and neck, with recurrence and distant metastasis being the primary causes of mortality among affected patients. Carcinoembryonic antigen cellular adhesion molecules (CEACAMs) are implicated in various physiological and pathophysiological processes. However, the role of CEACAM7 in NPC progression remains unclear. This study investigated the influence of CEACAM7 on NPC progression.</div></div><div><h3>Methods</h3><div>Cell migration and invasion ability were conducted using a Boyden chamber assay. Regulation of signaling pathways was evaluated by immunoblotting.</div></div><div><h3>Results</h3><div>The findings revealed that CEACAM7 is highly expressed in human NPC tissues, with particularly elevated levels observed in malignant tissues and high-grade squamous cell carcinoma tissues. Furthermore, CEACAM7 was demonstrated to regulate cell migration and invasion in human NPC cells but did not influence cell proliferation. Moreover, CEACAM7 enhanced cell motility through the activation of the JAK2/STAT3/BST2 signaling pathway. Notably, cotreatment with WP1066, a JAK2/STAT3 inhibitor, suppressed CEACAM7-induced cell migratory ability and downregulated BST2 expression in NPC cells.</div></div><div><h3>Conclusions</h3><div>These findings indicate that the CEACAM7/JAK2/STAT3/BST2 axis plays a crucial role in promoting NPC cell migration and underscore its potential as a therapeutic target for mitigating NPC metastasis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167948"},"PeriodicalIF":4.2,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144242230","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":"Calreticulin (crt-1) silencing reduces Aß1–42-induced toxicity and restores muscle function in C. elegans.","authors":"Elena Caldero-Escudero,&nbsp;Silvia Romero-Sanz,&nbsp;Pilar Álvarez-Illera,&nbsp;Sergio De la Fuente,&nbsp;Paloma García-Casas,&nbsp;Rosalba I. Fonteriz,&nbsp;Mayte Montero,&nbsp;Javier Álvarez,&nbsp;Jaime Santo-Domingo","doi":"10.1016/j.bbadis.2025.167946","DOIUrl":"10.1016/j.bbadis.2025.167946","url":null,"abstract":"<div><div>Accumulation of aggregated β-amyloid peptide is a key histopathological feature of Alzheimer's Disease (AD). Experimental models of AD based on β-amyloid peptide display calcium (Ca²⁺) signaling alterations, and targeting key components of the cellular Ca²⁺ signaling system has been postulated to modulate AD onset and progression. Here we have taken advantage of a <em>C. elegans</em> strain that over-expresses the most toxic human ß-amyloid peptide (Aß₁_–₄₂) in body-wall muscle cells, to study the impact of calreticulin (<em>crt-1</em>) silencing on body-wall muscle performance. <em>Crt-1</em> knockdown reduced the percentage of paralyzed worms in a dose-dependent manner and improved locomotion parameters in free-mobility assays in Aß₁_–₄₂-overexpressing worms. At the cellular level, <em>crt-1</em> silencing prevented Aß₁_–₄₂-induced exacerbated mitochondrial respiration and mitochondrial ROS production without impacting mitochondrial sarcomere organization. <em>Crt-1</em> knockdown reduced the number and size of Aß₁_–₄₂ aggregates in body-wall muscle cells and prevented the formation of Aß₁_–₄₂ oligomers. We propose that <em>crt-1</em> depletion reduces the number of Aß₁_–₄₂ aggregates, precluding Aß₁_–₄₂-induced mitochondrial toxicity and improving muscle function. We identify <em>C. elegans crt-1</em> as a gene involved in the toxicity associated with the expression of human Aß₁_–₄₂, and thus a potential new target for treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167946"},"PeriodicalIF":4.2,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222247","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":"Microglia-drive IRF8 upregulates complement pathway in Parkinson's disease","authors":"Hongkai Yao ,&nbsp;Chenming Liu ,&nbsp;Lingjing Jin ,&nbsp;Yunping Song","doi":"10.1016/j.bbadis.2025.167928","DOIUrl":"10.1016/j.bbadis.2025.167928","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a widespread degenerative disorder of the central nervous system. The gradual degeneration of dopaminergic neurons in the substantia nigra region is one of the primary pathological features of PD. Glial cells in SN are also linked to the pathological PD alterations. To discern the role of neurons and glial cells as well as their corresponding genetic modifications in PD, we utilized diverse bioinformatics techniques and performed biological experiments on cell and animal models. Several transcriptome datasets of the substantia nigra region were collected from the Gene Expression Omnibus dataset. Cibersort was used to deconvolute the data into proportions of brain cell types. WGCNA was used to analyze the association between modules and traits. Machine learning was used to select the hub genes from WGCNA results. Based on the results of transcriptome analysis, microglia were the most related cell type. Through machine learning, IRF8 was identified as the hub gene associated with PD and microglia. Furthermore, an increased ratio of IRF8+ microglia was observed in PD mice, along with an elevated expression of IRF8 in primary microglia cultures treated with α-synuclein preformed fibril (PFFs). To explore the function of IRF8 in microglia under disease condition, we conducted siRNA of IRF8 and found it was highly associated with complement pathway, which may cause the activation of microglia. In conclusion, our research indicated IRF8 may be involved in the functional regulation of microglia in PD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167928"},"PeriodicalIF":4.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190486","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":"Single-cell RNA-seq reveals the immune profile changes in patients with diarrhoeal-irritable bowel syndrome","authors":"Xiaoxuan Xue ,&nbsp;Juncong Hu ,&nbsp;Wenjing Pei ,&nbsp;Tangyou Mao ,&nbsp;Yali Yuan ,&nbsp;Yang Zhang ,&nbsp;Yupu Yao ,&nbsp;Lei Wang ,&nbsp;Chune Xie ,&nbsp;Junxiang Li ,&nbsp;Xingjie Zhao","doi":"10.1016/j.bbadis.2025.167945","DOIUrl":"10.1016/j.bbadis.2025.167945","url":null,"abstract":"<div><h3>Background</h3><div>Diarrhea-predominant irritable bowel syndrome (IBS-D) is characterized by recurrent abdominal pain and chronic diarrhea. T lymphocytes, which play a crucial role in gut inflammation and immune responses, may significantly contribute to the pathophysiology of IBS-D. However, the exact mechanisms by which T lymphocytes affect IBS-D remain unclear. The precise pathways and interactions involved in IBS-D are still to be determined.</div></div><div><h3>Methods</h3><div>We conducted single-cell RNA sequencing on blood samples from 4 IBS-D patients and 4 healthy controls. Following data preprocessing, we conducted subsequence bioinformatics analysis. Additionally, serum and colon tissue samples from IBS-D rat models were analyzed using ELISA and three-parameter fluorescence to further elucidate the T lymphocytes landscape associated with IBS-D.</div></div><div><h3>Results</h3><div>A total of 45,649 cells were classified into four distinct cell types. Among them, T lymphocytes were further subdivided into 20 unique clusters. Novel markers that were highly expressed in T lymphocytes were identified. Dysregulation of HIF-1α pathway, NF-kappa B pathway, and IL-17 signaling pathway, were observed through trajectory analysis. Additionally, single-cell regulatory network inference and clustering analysis revealed the FOS signaling pathway as a potential therapeutic target for IBS-D. Furthermore, we detected abnormally elevated levels of PLK3 and NFKBIZ in the serum and colon tissues of the IBS-D rat model. Our study mapped the communication atlas of T lymphocytes that may influence the pathophysiology of IBS-D.</div></div><div><h3>Conclusions</h3><div>This study uncovers novel molecular features and identifies potential therapeutic targets of T lymphocytes in IBS-D, thereby advancing our understanding of the disease and expanding treatment options.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167945"},"PeriodicalIF":4.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210472","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":"Extracellular vesicle-dependent crosstalk between hepatic stellate cells and Kupffer cells promotes their mutual activation","authors":"Junyu Wang ,&nbsp;Jia Li ,&nbsp;Manon Buist-Homan ,&nbsp;Martin C. Harmsen ,&nbsp;Han Moshage","doi":"10.1016/j.bbadis.2025.167914","DOIUrl":"10.1016/j.bbadis.2025.167914","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Hepatic fibrosis results from hepatic stellate cell (HSC) activation and excessive extracellular matrix (ECM) deposition, driven by chronic inflammation. Kupffer cells (KCs) play a central role in HSC activation. We previously showed that HSC-secreted factors, particularly extracellular vesicles (EVs), activate KCs. However, the reciprocal effects of activated KCs on HSCs remain poorly understood. This study investigates the bidirectional crosstalk between HSCs and KCs, focusing on the role of KC-derived EVs in regulating HSC activation and fibrosis progression.</div></div><div><h3>Methods</h3><div>Primary HSCs and KCs were isolated from male Wistar rats. HSCs were co-cultured with KCs for 24 h to assess inflammatory and activation markers. LPS-stimulated KC-derived EVs and controls were administered to HSCs on day 1. LPS and the Toll-like receptor 4 (TLR4) inhibitor TAK-242 were used to investigate the intercellular communication in detail.</div></div><div><h3>Results</h3><div>Co-cultured HSCs and KCs showed mutual activation, demonstrated by elevated inflammatory markers in both cell types and enhanced HSC pro-fibrotic activation. Pro-inflammatory (LPS)-activated KCs amplified HSC activation in a TLR4-dependent fashion. Part of this augmented HSC activation was attributed to EVs.</div></div><div><h3>Conclusions</h3><div>In co-culture, KCs and HSCs show mutual activation in a TLR4-dependent fashion. This bidirectional activation is augmented by pro-inflammatory mediators. KC-derived EVs (partially) activate HSCs, which might contribute to progression of liver fibrosis <em>in vivo</em>. Modulating KC activation, such as by blocking TLR4 signaling, may alter EV secretion or cargo composition, reducing HSC activation and fibrosis progression. Targeting this EV-mediated crosstalk could provide novel therapeutic strategies for liver fibrosis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167914"},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168478","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}