Metabolism: clinical and experimental最新文献

{"title":"Unraveling sphingolipid complexity in liver fibrosis: Perspectives for future research.","authors":"Jiaqi Wei, Yaohui Zhong, Yaling Li, Jun Li","doi":"10.1016/j.metabol.2025.156254","DOIUrl":"https://doi.org/10.1016/j.metabol.2025.156254","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156254"},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hexosamine biosynthesis dysfunction-induced LIFR N-glycosylation deficiency exacerbates steatotic liver ischemia/reperfusion injury","authors":"Ran Liu ,&nbsp;Gengqiao Wang ,&nbsp;Yongbing Qian ,&nbsp;Zhengting Jiang ,&nbsp;Weimin Wang ,&nbsp;Mao Cai ,&nbsp;Shuhua Zhang ,&nbsp;Guoliang Wang ,&nbsp;Chuanzheng Wang ,&nbsp;Tianhao Zou ,&nbsp;Huan Cao ,&nbsp;Di Zhang ,&nbsp;Xueling Wang ,&nbsp;Shenghe Deng ,&nbsp;Tongxi Li ,&nbsp;Jinyang Gu","doi":"10.1016/j.metabol.2025.156258","DOIUrl":"10.1016/j.metabol.2025.156258","url":null,"abstract":"<div><h3>Background</h3><div>More and more steatotic livers undergo resection or transplantation but they exhibit higher susceptibility to ischemia-reperfusion injury (IRI), which results in increased perioperative complication morbidity and mortality. IRI is driven by various cytokines and receptors, both of which are extensively modified by N-glycosylation. We aim to elucidate susceptibility of steatotic livers to IRI from the perspective of N-glycosylation.</div></div><div><h3>Methods</h3><div>Differentially expressed genes and glycoproteins were identified with RNA-seq and N-glycoproteomics. Myeloid LIF or hepatocyte LIFR knockout mice were developed to examine the function of LIF and LIFR. Modalities including phosphoproteomics, ChIP-seq, single cell RNA-seq, metabolomics and immunoblotting were utilized to investigate underlying mechanisms.</div></div><div><h3>Results</h3><div>LIF transcription in myeloid cells and LIFR N-glycosylation in hepatocytes were substantially induced by IRI of normal livers. LIF and LIFR protected normal livers from IRI through activating STAT3 and promoting downstream TNFAIP3 expression, which was facilitated by LIFR N-glycosylation. Mechanistically, N-glycosylation at N238 stabilized LIFR protein by disrupting TRIM28-mediated K48 ubiquitination at LIFR K254. Furthermore, N-glycosylation at N358/N658/N675 of LIFR facilitated LIF/LIFR/gp130 complex formation and subsequent signal transduction. However, in steatotic livers, myeloid cell LIF transcription was partially inhibited due to hepatic microenvironment L-arginine insufficiency, while hepatocyte LIFR N-glycosylation was defective due to intracellular UDP-GlcNAc exhaustion. Importantly, combined L-arginine and GlcNAc treatment reversed LIF expression and LIFR N-glycosylation insufficiency, which represents potential therapeutic strategy to protect steatotic livers.</div></div><div><h3>Conclusions</h3><div>LIF expression and LIFR N-glycosylation insufficiency aggravates steatotic liver IRI, which can be reversed by combined L-arginine and GlcNAc treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156258"},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L-Kynurenine activates the AHR-PCSK9 pathway to mediate the lipid metabolic and ovarian dysfunction in polycystic ovary syndrome","authors":"Yujiao Wang ,&nbsp;Yifan Wu ,&nbsp;Hongwei Jiang ,&nbsp;Shang Li ,&nbsp;Jingjing Li ,&nbsp;Cong Wang ,&nbsp;Lexin Yang ,&nbsp;Xiying Zhou ,&nbsp;Juanjuan Yu ,&nbsp;Junyu Zhai ,&nbsp;Zi-Jiang Chen ,&nbsp;Yanzhi Du","doi":"10.1016/j.metabol.2025.156238","DOIUrl":"10.1016/j.metabol.2025.156238","url":null,"abstract":"<div><div>Dysregulated amino acid metabolism is a key contributor to polycystic ovary syndrome (PCOS). This cross-sectional study revealed that serum levels of L-kynurenine (L-Kyn) were significantly elevated in women with PCOS, whereas pyridoxal 5′-phosphate (PLP) levels were markedly reduced. Moreover, human serum L-Kyn levels exhibited a positive correlated with low-density lipoprotein cholesterol (LDL-C) and a negative correlation with high-density lipoprotein cholesterol (HDL-C). Additionally, letrozole (LET) induced PCOS-like mice displayed increased hepatic L-Kyn levels. Mechanistically, both in vivo and in vitro experiments demonstrated that the upregulation of indoleamine 2,3-dioxygenase (IDO1) activates the aryl hydrocarbon receptor (AHR) - proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway in the liver of PCOS-like mice, thereby contributing to dyslipidemia. Treatment with epacadostat, an inhibitor of the enzyme IDO1, or PLP, a cofactor for L-Kyn catabolism, effectively restored ovarian function, improved glucose tolerance, and ameliorated lipid profile abnormalities in PCOS-like mice.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156238"},"PeriodicalIF":10.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevention of insulin-induced lipohypertrophy by coadministration of a low dose of high-affinity PI3K inhibitors","authors":"Barbara Becattini ,&nbsp;Andrea Usseglio Gaudi ,&nbsp;Per-Anders Jansson ,&nbsp;Giovanni Solinas","doi":"10.1016/j.metabol.2025.156252","DOIUrl":"10.1016/j.metabol.2025.156252","url":null,"abstract":"<div><h3>Background</h3><div>Insulin-induced lipohypertrophy (ILH) is the most frequent injection site side effect of insulin therapy. ILH consists of local adipose tissue overgrowth at the insulin injection site that eventually progresses to lipoma-like masses of a relatively large size, causing discomfort and disfiguration. Insulin injection into ILH areas delays insulin delivery, and the presence of ILH is associated with poor glycemic control and more frequent hypoglycemic events. Although, in principle, the development of ILH can be minimized by avoiding injecting insulin in the same spot, in practice, ILH remains highly prevalent. So far, no molecular mechanism for ILH has been proposed.</div></div><div><h3>Methods</h3><div>We screened a panel of PI3K inhibitors with different specificities for their capacity to reduce insulin signaling and growth of human primary adipocytes exposed to pharmacological doses of insulin. The two most effective inhibitors from the screening above were investigated in an in-vivo model of ILH.</div></div><div><h3>Results</h3><div>We identified PI3K inhibitors capable of reducing the hypertrophic (enlargement of lipid droplets) and hyperplastic (adipocyte differentiation) growth of primary human adipocytes exposed to pharmacological doses of insulin. Since preventing ILH development requires only a localized inhibition of PI3K activity, using a low dose of high-affinity PI3K inhibitors, we could prevent the development of ILH in a mouse model without inhibiting the systemic effects of insulin on blood glucose and without causing any apparent adverse reaction.</div></div><div><h3>Conclusion</h3><div>We now show evidence indicating that ILH is caused by pathological PI3K activation at insulin injection sites and that ILH can be prevented by local inhibition of PI3K activity at the injection site.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156252"},"PeriodicalIF":10.8,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic dysfunction-associated steatotic liver disease and malignancies: Unmasking a silent saboteur","authors":"Stergios A. Polyzos ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156253","DOIUrl":"10.1016/j.metabol.2025.156253","url":null,"abstract":"<div><div>Not required for Editorials.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156253"},"PeriodicalIF":10.8,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-sarcopenic effects of active vitamin D through modulation of anabolic and catabolic signaling pathways in human skeletal muscle: A randomized controlled trial","authors":"Tetsuya Kawahara ,&nbsp;Tetsuya Inazu ,&nbsp;Shoichi Mizuno ,&nbsp;Naoki Tominaga ,&nbsp;Mikio Toda ,&nbsp;Nagahiro Toyama ,&nbsp;Chie Kawahara ,&nbsp;Gen Suzuki ,&nbsp;the DPVD Research Group","doi":"10.1016/j.metabol.2025.156240","DOIUrl":"10.1016/j.metabol.2025.156240","url":null,"abstract":"<div><h3>Background</h3><div>The muscle-building and strengthening effects of the active form of vitamin D in humans remain unclear.</div></div><div><h3>Methods</h3><div>In this ancillary study of the Diabetes Prevention with active Vitamin D trial, we examined clinical and experimental aspects to investigate the effects and mechanisms of eldecalcitol, an active form of vitamin D, in preventing sarcopenia. We examined changes in molecules involved in muscle synthesis and degradation pathways in muscle samples from 32 participants before and after 1 year of eldecalcitol or placebo treatment. The protein levels of molecules involved in muscle synthesis and degradation pathways were examined using western blotting. Additionally, the skeletal muscle and body fat volumes were measured using bioelectrical impedance analysis with a body composition analyzer.</div></div><div><h3>Results</h3><div>We found that eldecalcitol treatment for 1 year resulted in higher phosphorylation levels of mTOR and FOXO1 signaling pathways, which are associated with increased muscle mass and strength than those with placebo treatment. Body composition measurements at 1 year showed that the eldecalcitol group had significantly higher skeletal muscle mass (1.9 % vs. −3.4 %, <em>p</em> = 3.26E−9) and muscle strength (4.1 % vs. −0.7 %, <em>p</em> = 2.57E−17), and lower fat mass (−3.2 % vs. 1.8 %, <em>p</em> = 1.73E−12) than those in the placebo group.</div></div><div><h3>Conclusion</h3><div>This study suggested that the active form of vitamin D regulates the protein synthesis and degradation pathways in human skeletal muscle and may help prevent sarcopenia. This study was registered at UMIN clinical trials registry, UMIN 000005394.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156240"},"PeriodicalIF":10.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-C motif chemokines ligand 7 contributes to metabolic dysfunction-associated steatotic liver disease by enabling redox-sensitive induction of hypermethylated in cancer 1","authors":"Xinyue Sun ,&nbsp;Jinge Wu ,&nbsp;Huiqian Lv ,&nbsp;Ben Wang ,&nbsp;Xuelian Chen ,&nbsp;Wenjing Ren ,&nbsp;Xiulian Miao ,&nbsp;Yan Guo ,&nbsp;Xiaocen Kong ,&nbsp;Huihui Xu ,&nbsp;Zeqing Bao ,&nbsp;Yong Xu ,&nbsp;Zilong Li","doi":"10.1016/j.metabol.2025.156242","DOIUrl":"10.1016/j.metabol.2025.156242","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global pandemic and the most critical implication for liver transplantation. In the present study, we investigated the role of C<img>C motif chemokine ligand 7 (CCL7) in MASLD pathogenesis focusing on mechanism and translational potential. We report that CCL7 blockade with a neutralization antibody attenuated MASLD in mice. RNA-seq performed in hepatocytes identified hypermethylated in cancer 1 (HIC1) as a novel target gene responsive to CCL7 treatment. CCL7 induced HIC1 expression was mediated by steroid receptor co-activator 1 (SRC-1) in a redox-sensitive manner. Mechanistically, enhanced ROS production by CCL7 activated protein kinase C theta (PKCθ), which in turn phosphorylated SRC-1 thereby enabling SRC-1 recruitment to the <em>Hic1</em> promoter. Consistently SRC-1 depletion or HIC1 depletion ameliorated MASLD in mice. Further analysis revealed that SRC-1 activated <em>Hic1</em> transcription in part by recruiting protein arginine methyltransferase 4 (PRMT4) in a redox-sensitive and phosphorylation-dependent manner. Importantly, pharmaceutical inhibition of PRMT4 activity with a small-molecule compound TP-064 mitigated MASLD in mice. Finally, relevance of the CCL7-SRC-1-PRMT4-HIC1 axis was confirmed in MASLD patients. In conclusion, our data uncover a previously unrecognized redox-sensitive mechanism underlying MASLD pathogenesis and present druggable targets for MASLD intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156242"},"PeriodicalIF":10.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Landscape of sex differences in obesity and type 2 diabetes in subcutaneous adipose tissue: a systematic review and meta-analysis of transcriptomics studies","authors":"Roxana Andreea Moldovan ,&nbsp;Marta R. Hidalgo ,&nbsp;Helena Castañé ,&nbsp;Andrea Jiménez-Franco ,&nbsp;Jorge Joven ,&nbsp;Deborah J. Burks ,&nbsp;Amparo Galán ,&nbsp;Francisco García-García","doi":"10.1016/j.metabol.2025.156241","DOIUrl":"10.1016/j.metabol.2025.156241","url":null,"abstract":"<div><div>Obesity represents a significant risk factor in the development of type 2 diabetes (T2D), a chronic metabolic disorder characterized by elevated blood glucose levels, and a previous step for its development. Significant sex differences have been identified in the prevalence, development, and pathophysiology of obesity and T2D; however, the underlying molecular mechanisms remain unclear. This study aims to identify sex-specific signatures in obesity and T2D and enhance our understanding of the underlying mechanisms associated with sex differences by integrating expression data.</div><div>We performed a systematic review and individual transcriptomic analysis of eight selected studies which included 302 subcutaneous adipose tissue samples. Then, we conducted different gene-level meta-analyses and functional characterizations for obesity and T2D separately, identifying common and sex-specific transcriptional profiles, many of which were previously associated with obesity or T2D.</div><div>The obesity meta-analysis yielded nineteen differentially-expressed genes from a sex-specific perspective (e.g., <em>SPATA18</em>, <em>KREMEN1</em>, <em>NPY4R</em>, and <em>PRM3</em>), while a comparison of the expression profiles between sexes in T2D prompted the identification and validation of specific transcriptomic signatures in males (<em>SAMD9</em>, <em>NBPF3</em>, <em>LDHD</em>, and <em>EHD3</em>) and females (<em>RETN</em>, <em>HEY1</em>, <em>PLPP2</em>, and <em>PM20D2</em>). At the functional level, we highlighted the fundamental role of the Wnt pathway in the development of obesity and T2D in females, and the roles of mitochondrial damage and free fatty acids in males.</div><div>Overall, our sex-specific meta-analyses supported the detection of differentially expressed genes in males and females associated with the development of obesity and further T2D development, emphasizing the relevance of sex-based information in biomedical data and opening new avenues for research.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156241"},"PeriodicalIF":10.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity","authors":"Aleix Ribas-Latre ,&nbsp;Anne Hoffmann ,&nbsp;Claudia Gebhardt ,&nbsp;Juliane Weiner ,&nbsp;Lilli Arndt ,&nbsp;Nora Raulien ,&nbsp;Martin Gericke ,&nbsp;Adhideb Ghosh ,&nbsp;Kerstin Krause ,&nbsp;Nora Klöting ,&nbsp;Paul T. Pfluger ,&nbsp;Bilal N. Sheikh ,&nbsp;Thomas Ebert ,&nbsp;Anke Tönjes ,&nbsp;Michael Stumvoll ,&nbsp;Christian Wolfrum ,&nbsp;Matthias Blüher ,&nbsp;Ulf Wagner ,&nbsp;Joan Vendrell ,&nbsp;Sonia Fernández-Veledo ,&nbsp;John T. Heiker","doi":"10.1016/j.metabol.2025.156239","DOIUrl":"10.1016/j.metabol.2025.156239","url":null,"abstract":"<div><div>Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that <em>Klk7</em> deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156239"},"PeriodicalIF":10.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial lipidomics reveals sphingolipid metabolism as anti-fibrotic target in the liver","authors":"Aleksandra Gruevska ,&nbsp;Jack Leslie ,&nbsp;Elena Perpiñán ,&nbsp;Hannah Maude ,&nbsp;Amy L. Collins ,&nbsp;Sophia Johnson ,&nbsp;Laila Evangelista ,&nbsp;Eleanor Sabey ,&nbsp;Jeremy French ,&nbsp;Steven White ,&nbsp;John Moir ,&nbsp;Stuart M. Robinson ,&nbsp;Wasfi Alrawashdeh ,&nbsp;Rohan Thakkar ,&nbsp;Roberta Forlano ,&nbsp;Pinelopi Manousou ,&nbsp;Robert Goldin ,&nbsp;David Carling ,&nbsp;Matthew Hoare ,&nbsp;Mark Thursz ,&nbsp;Zoe Hall","doi":"10.1016/j.metabol.2025.156237","DOIUrl":"10.1016/j.metabol.2025.156237","url":null,"abstract":"<div><h3>Background and aims</h3><div>Steatotic liver disease (SLD), which encompasses various causes of fat accumulation in the liver, is a major cause of liver fibrosis. Understanding the specific mechanisms of lipotoxicity, dysregulated lipid metabolism, and the role of different hepatic cell types involved in fibrogenesis is crucial for therapy development.</div></div><div><h3>Methods</h3><div>We analysed liver tissue from SLD patients and 3 mouse models. We combined bulk/spatial lipidomics, transcriptomics, imaging mass cytometry (IMC) and analysis of published spatial and single-cell RNA sequencing (scRNA-seq) data to explore the metabolic microenvironment in fibrosis. Pharmacological inhibition of sphingolipid metabolism with myriocin, fumonisin B1, miglustat and D-PDMP was carried out in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs).</div></div><div><h3>Results</h3><div>Bulk lipidomics revealed increased glycosphingolipids, ether lipids and saturated phosphatidylcholines in fibrotic samples. Spatial lipidomics detected &gt;40 lipid species enriched within fibrotic regions, notably sphingomyelin (SM) 34:1. Using bulk transcriptomics (mouse) and analysis of published spatial transcriptomics data (human) we found that sphingolipid metabolism was also dysregulated in fibrosis at transcriptome level, with increased gene expression for ceramide and glycosphingolipid synthesis. Analysis of human scRNA-seq data showed that sphingolipid-related genes were widely expressed in non-parenchymal cells. By integrating spatial lipidomics with IMC of hepatic cell markers, we found excellent spatial correlation between sphingolipids, such as SM(34:1), and myofibroblasts. Inhibiting sphingolipid metabolism resulted in anti-fibrotic effects in HSCs and hPCLSs.</div></div><div><h3>Conclusions</h3><div>Our spatial multi-omics approach suggests cell type-specific mechanisms of fibrogenesis involving sphingolipid metabolism. Importantly, sphingolipid metabolic pathways are modifiable targets, which may have potential as an anti-fibrotic therapeutic strategy.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156237"},"PeriodicalIF":10.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}