Journal of Cell Communication and Signaling最新文献

{"title":"Report on the 13th international workshop on the CCN family of genes and inaugural ARBIOCOM conference, Nice, France","authors":"Bernard Perbal,&nbsp;Ralf Weiskirchen,&nbsp;Annick Perbal,&nbsp;Brahim Chaqour","doi":"10.1002/ccs3.70096","DOIUrl":"10.1002/ccs3.70096","url":null,"abstract":"<p>The 13th International Workshop on the CCN Family of Genes, held in Nice as part of the inaugural ARBIOCOM World Conference, brought together investigators with diverse research backgrounds, disciplines, and expertise. Building on the long-standing mission of the International CCN Society and the expanding ARBIOCOM initiative, the meeting highlighted the growing importance of interdisciplinary exchange in accelerating discovery in normal and pathological signaling networks. Scientific sessions featured presentations by renowned speakers and early-career investigators alike, creating a highly collaborative environment that fostered discussion of emerging concepts and translational opportunities. Among the major themes, this joint conference-meeting highlighted “hot” research topics such as the nuclear and extracellular roles of CCN proteins in regulating gene expression, tissue development and remodeling, stem cell differentiation and therapies, and disease initiation and progression. Presentations on skeletal biology emphasized how extracellular matrix proteins and matricellular factors shape bone, cartilage, and connective tissue development and pathology, whereas vascular sessions revealed new mechanistic links between extracellular cues, endothelial remodeling, macrophage-driven vessel regression and vascular smooth muscle homeostasis. Other talks extended the relevance of new signaling molecules in intestinal regeneration, hepatic inflammation, metabolic control, and cancer progression, illustrating the broad biological reach of these pathways. The meeting also emphasized the value of integrating new model systems, advanced single-cell approaches, and functional in vivo studies to uncover mechanisms that were previously unknown. Collectively, the scientific sessions and discussions identified and filled key knowledge gaps and generated new hypotheses with strong potential for future discoveries. By connecting established expertise with complementary scientific perspectives, this meeting provided a fertile platform for cross-pollination of ideas and highlighted several avenues for future research aimed at developing novel diagnostic and therapeutic strategies and tools.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alcohol exposure promotes cell communication network 1 cleavage in esophageal adenocarcinoma cells exclusively","authors":"Wula Aladan,&nbsp;Baoxin Chi,&nbsp;Zhiheng Chang,&nbsp;Mizhu Wang,&nbsp;Tong Dang,&nbsp;Xianmei Meng,&nbsp;Jianyuan Chai","doi":"10.1002/ccs3.70103","DOIUrl":"10.1002/ccs3.70103","url":null,"abstract":"<p>Alcohol consumption has been a risk factor for more than 200 diseases, including esophageal cancer. Cell communication network 1 (CCN1), a matricellular protein, is highly expressed in esophageal squamous cell carcinoma (ESCC) but is barely detectable in esophageal adenocarcinoma (EAC). Alcohol consumption has been identified as a major contributor to ESCC development, but its role in EAC is uncertain. This study examines the impact of acute (30 min) or prolonged (12 h) alcohol exposure (5, 100, and 500 mM) on CCN1 expression and function in esophageal epithelial cells, including normal (HEEC), ESCC (KYSE150 and KYSE410), and EAC (OE19 and OE33), in association with the activity of MMP2, MMP9, and MMP14. It was found that alcohol exposure promoted CCN1 expression in both normal and tumor cells but induced CCN1 cleavage exclusively in EAC cells, generating an 18-kDa fragment that promotes tumor growth. MMP9, which was active only in EAC cells, was found to mediate this cleavage. Forced activation of MMP9 in either normal or ESCC cells improved cell viability, whereas inhibition of MMP9 in EAC cells attenuated cell survival. Taken together, alcohol exposure promotes MMP9-mediated CCN1 cleavage in EAC, converting CCN1 from a pro-death to a pro-survival factor for EAC. This makes alcohol consumption a risk factor not only for ESCC development but also for EAC progression. A preprint can be found at d197for5662m48.cloudfront.net.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 suppressor of cytokine signaling 3 regulates glioma stem cell maintenance and immune microenvironment through signal transducer and activator of transcription 3 signaling","authors":"Jingtao Wang,&nbsp;Gaolei Hou,&nbsp;Zhaofei Song,&nbsp;Kai Gao,&nbsp;Hongbin Wang,&nbsp;Tao Li","doi":"10.1002/ccs3.70041","DOIUrl":"https://doi.org/10.1002/ccs3.70041","url":null,"abstract":"<p>This study aims to elucidate the role of suppressor of cytokine signaling 3 (SOCS3) in glioma stem cells (GSCs) via single-cell RNA sequencing (scRNA-seq), focusing on its regulation of STAT3-mediated self-renewal, apoptosis resistance, and tumor microenvironment (TME) remodeling. ScRNA-seq data from 19 high-grade glioma patients were analyzed using Seurat, Harmony, and SingleR for clustering, annotation, and SOCS3 stratification (SOCS3-High: <i>n</i> = 4; SOCS3-Low: <i>n</i> = 15). Differential gene analysis, pathway enrichment, and CellChat were employed for TME characterization. In vitro, SOCS3-overexpressing/silenced GSC11 models were tested via MTT, TUNEL, neurosphere assays, and STAT3 pathway modulation (IL-6). In vivo, intracranial xenografts in nude mice evaluated tumor growth and survival. SOCS3 was downregulated in GSCs and neurons. SOCS3-Low GSCs exhibited 777 differentially expressed genes enriched in T-cell receptor, p53, and JAK-STAT axis, suppressed T-cell/microglia infiltration, and promoted oligodendrocyte precursor cell/astrocyte survival. SOCS3 overexpression reduced GSC proliferation, induced apoptosis, inhibited neurosphere formation, and suppressed STAT3 phosphorylation and stemness markers (OCT4/SOX2/NANOG). IL-6 reactivated STAT3, reversing SOCS3-mediated tumor suppression. In vivo, SOCS3 overexpression attenuated tumor growth and prolonged survival, counteracted by IL-6. Low SOCS3 expression contributes to glioma progression by promoting STAT3 activation and an immunosuppressive TME. Targeting the SOCS3-STAT3 axis may offer therapeutic potential.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccs3.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148647661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-22Rα1 restrains pancreatic injury independently of its C-terminal STAT3-amplifying domain","authors":"Léna Puigdevall,&nbsp;Clara Stewardson,&nbsp;Lysa Dhulst,&nbsp;Emilie Hendrickx,&nbsp;Laure Dumoutier","doi":"10.1002/ccs3.70098","DOIUrl":"https://doi.org/10.1002/ccs3.70098","url":null,"abstract":"<p>Interleukin-22 (IL-22) is a cytokine that regulates tissue inflammation and repair, primarily through activation of STAT3 signaling. Although its protective effects in acute pancreatitis (AP) are well established, the specific contribution of its receptor, IL-22Ra1, and the underlying signaling mechanisms remain incompletely defined. Notably, the C-terminal region of IL-22Ra1, although devoid of tyrosine residues, has been reported to promote STAT3 activation through unconventional mechanisms. Here, we investigated the role of IL-22Ra1 and its C-terminal (STAT3-associated) domain in a mouse model of caerulein-induced AP. We show that deletion of the C-terminal region of IL-22Ra1 markedly reduces STAT3 activation in the pancreas, confirming its role in amplifying canonical signaling. Unexpectedly, this reduction does not worsen pancreatic injury. In contrast, both IL-22- and IL-22Ra1-deficient mice develop more severe pancreatitis, characterized by increased serum amylase levels, exacerbated inflammatory responses, and enhanced tissue damage. Notably, IL-22Ra1 deficiency results in a more severe phenotype than IL-22 deficiency alone, indicating that IL-22Ra1 mediates protective effects beyond IL-22 signaling. Consistently, acinar-to-ductal metaplasia during the regenerative phase is impaired in both IL-22- and IL-22Ra1-deficient mice but preserved upon C-terminal truncation. Together, these findings identify IL-22Ra1 as a central regulator of pancreatic protection through mechanisms that are independent of maximal STAT3 activation and extend beyond IL-22 itself, suggesting the involvement of additional IL-22Ra1 ligands. These results support the exploration of receptor-activating strategies, such as agonistic antibodies, to promote tissue protection and regeneration.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccs3.70098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic potential of B-cell translocation gene 2 in IgA nephropathy: Insights from molecular mechanisms","authors":"Min Kou,&nbsp;Mo Dan,&nbsp;Juan Cheng,&nbsp;Sheng Ge,&nbsp;Ruimin Ren","doi":"10.1002/ccs3.70082","DOIUrl":"10.1002/ccs3.70082","url":null,"abstract":"<p>IgA nephropathy (IgAN) is a prevalent glomerular disease characterized by IgA deposition, chronic inflammation, and fibrosis, leading to end-stage renal disease. This study explored B-cell translocation gene 2 (BTG2) as a biomarker and treatment target for IgAN progression. Through integrated expression datasets and functional analyses, BTG2 emerged as a key gene with downregulation in renal tissues of IgAN patients, showing high diagnostic accuracy. BTG2 influenced the immune microenvironment by modulating T follicular helper cells and M0 macrophages. Moreover, BTG2 overexpression mitigated IgA deposition and fibrosis, whereas its silencing exacerbated these pathological changes. The study highlights BTG2 as a promising diagnostic tool and therapeutic target, shedding light on potential treatment strategies for IgAN.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148603383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to an immunometabolism-related signature for renal clear cell carcinoma diagnosis and therapeutic target","authors":"","doi":"10.1002/ccs3.70097","DOIUrl":"https://doi.org/10.1002/ccs3.70097","url":null,"abstract":"&lt;p&gt;Hu, Guofan, Jian Liang, Meiling Feng, Hansheng Lin, and Jingwei He. 2025. “An Immunometabolism-Related Signature for Renal Clear Cell Carcinoma Diagnosis and Therapeutic Target.” &lt;i&gt;Journal of Cell Communication and Signaling&lt;/i&gt;: e70047. https://doi.org/10.1002/ccs3.70047.&lt;/p&gt;&lt;p&gt;In the original article, the incorrect version of the abstract was published. The correct version is published below. The online version of the article has been updated.&lt;/p&gt;&lt;p&gt;We apologize for this error.&lt;/p&gt;&lt;p&gt;Abstract&lt;/p&gt;&lt;p&gt;Kidney renal clear cell carcinoma (KIRC) lacks sensitive biomarkers for early diagnosis and effective guidance for personalized therapy. Given the close interplay between tumor metabolism and immune regulation, this study aimed to identify immunometabolism-related biomarkers for KIRC and develop a robust diagnostic model. Transcriptomic datasets from TCGA and GEO were integrated, and immunometabolism-related genes were collected from GeneCards. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis identified candidate genes, which were subsequently evaluated using 12 machine learning algorithms with 113 algorithmic combinations. The optimal model was selected through 10-fold cross-validation and validated in independent external cohorts. Additional analyses included immune infiltration, functional enrichment, single-cell RNA sequencing, drug sensitivity, and PD-L1 response assessments, while gene expression and biological functions were verified through TCGA, HPA, qRT-PCR, Western blotting, and experimental studies.&lt;/p&gt;&lt;p&gt;A total of 22 overlapping immunometabolism-related genes were identified. Among the 113 algorithmic combinations, the random forest model achieved the best performance and identified six key biomarkers: APOBEC3G, CD4, CSK, HLA-A, IFNGR2, and LDHB. The diagnostic model demonstrated excellent predictive accuracy, with AUC values of 0.998 in the training cohort, 0.991 in GSE36895, and 0.988 in GSE40435. These biomarkers were significantly associated with immune cell infiltration and enriched in immune-related pathways, including antigen presentation, PD-1/PD-L1 signaling, Th1/Th2 differentiation, and HIF-1 signaling. Single-cell analysis revealed distinct enrichment patterns across immune cell populations, while drug sensitivity analysis suggested potential interactions with gemcitabine, 5-fluorouracil, pembrolizumab, cisplatin, and SB216763. Expression validation showed that IFNGR2, CD4, CSK, HLA-A, and APOBEC3G were upregulated, whereas LDHB was downregulated in KIRC. Functional experiments demonstrated that silencing IFNGR2, CD4, CSK, HLA-A, or APOBEC3G, or overexpressing LDHB, significantly inhibited proliferation, migration, and invasion and promoted apoptosis in KIRC cells. In xenograft models, these interventions also markedly suppressed tumor growth.&lt;/p&gt;&lt;p&gt;Overall, six immunometabolism-related biomarkers were identified and integrated into a high-performing diagnostic model for KIRC. Thes","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccs3.70097","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling isoleucyl-tRNA synthetase 2 as a novel driver of breast cancer via β-catenin pathway activation","authors":"Xi Yang,&nbsp;Ya Wang,&nbsp;Yanjiao Yi,&nbsp;Yang Yang,&nbsp;Hongjiang Wang","doi":"10.1002/ccs3.70094","DOIUrl":"10.1002/ccs3.70094","url":null,"abstract":"<p>Breast cancer represents the most common malignant tumor in women globally. Isoleucyl-tRNA synthetase 2 (IARS2), a member of the aminoacyl-tRNA synthetase family, promotes tumorigenesis across various cancers. Herein, the effects and mechanisms of IARS2 in breast cancer were investigated. IARS2 is upregulated in breast cancer tissues compared to normal tissues, correlating with the poor prognosis of patients with breast cancer. In order to knock down and overexpress IARS2, plasmids carrying short hairpin RNA targeting IARS2 and IARS2-overexpression plasmids were transfected into breast cancer cells, respectively. Our results demonstrated that silencing IARS2 repressed breast cancer cell progression. IARS2 deficiency attenuated tumor growth in MDA-MB-231 cell xenograft mouse models. Conversely, overexpression of IARS2 aggravated malignant cell behaviors in vitro and accelerated tumor growth in vivo. Mechanistically, IARS2 depletion stimulated ubiquitination-mediated degradation of β-catenin in breast cancer cells. Notably, the β-catenin inhibitor XAV-939 reversed IARS2-driven breast cancer malignant progression. Furthermore, differentially expressed genes were identified in IARS2-overexpressed breast cancer cells with or without XAV-939 in the light of mRNA-seq results. Overall, our findings uncovered that silencing IARS2 blocked the β-catenin signaling axis, thereby impeding breast cancer progression. IARS2 might become a promising novel therapeutic target for breast cancer intervention.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma exosomal miR-339-3p promotes myocardial remodeling in chronic heart failure by regulating USP25-mediated DDX58 deubiquitination","authors":"Guoqiang Jing,&nbsp;Ting Xu,&nbsp;Yuhong Ma","doi":"10.1002/ccs3.70090","DOIUrl":"https://doi.org/10.1002/ccs3.70090","url":null,"abstract":"<p>To explore the mechanism by which plasma exosome miR-339-3p regulates myocardial remodeling in heart failure (HF). Plasma exosomes were isolated from 5 patients with HF and 5 controls, and cell uptake was determined by transmission electron microscopy, western blot and PKH26 labeling. Angiotensin II treated AC16 cells to induce cell hypertrophy. Cell counting kit-8 assay and flow cytometry were used to detect cell viability and apoptosis to evaluate the effect of HF-exo. High-throughput sequencing was performed on exosomal microRNAs to identify key differential mirnas (miR-339-3p), and database screening was used to verify downstream target proteins ubiquitin-specific protease 25 (USP25) by dual-luciferase reporter gene assay and reverse transcription-quantitative polymerase chain reaction/western blot. Searchtool for the retrieval of interacting genes, the Cancer Genome Atlas and co-immunoprecipitation were used to screen USP25-interacting proteins (DDX58). Analysis revealed that inhibition of miR-339-3p completely reversed cardiomyocyte injury induced by HF-exo. miR-339-3p directly targets USP25, down-regulates its expression, and impairs its K48-related DDX58 deubiquitination. Overexpression of USP25 can reverse myocardial injury induced by mir-339-3p, and DDX58 silencing can eliminate the protective effect of USP25. Plasma exosome miR-339-3p promotes myocardial remodeling in HF through the miR-339-3p-USP25-DDX58 axis and is a potential target for the diagnosis and treatment of HF.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccs3.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to Regulation of phosphatase and tensin homolog by complement component 5a (C5a) and its receptor (C5aR 1) in lupus nephritis: A novel therapeutic target","authors":"","doi":"10.1002/ccs3.70087","DOIUrl":"https://doi.org/10.1002/ccs3.70087","url":null,"abstract":"<p>Ma, Yuehong, YiWang, PengZhao, et al. 2025. “Regulation of Phosphatase and Tensin Homolog by Complement Component 5a (C5a) and Its Receptor (C5aR 1) in Lupus Nephritis: A Novel Therapeutic Target,” <i>Journal of Cell Communication and Signaling</i>: e70055. https://doi.org/10.1002/ccs3.70055.</p><p>In the originally published article, the first panel is missing from Figure 5e. The corrected figure is shown below. Additionally, throughout the article, “LNn” has been changed to “Ln” and “C5aR11” has been changed to “C5aR 1.” The online version of the article has been updated.</p><p>We apologize for this error.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 2","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccs3.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ceramide-mediated mitochondrial dysfunction in nonobese nonalcoholic fatty liver disease: A regulatory role for serine palmitoyltransferase subunit 2","authors":"Li-Jun Xue,&nbsp;Guang-Yan Yao,&nbsp;Fei-Fei Fan,&nbsp;Kai-Min Li,&nbsp;Wen-Ming Wu","doi":"10.1002/ccs3.70091","DOIUrl":"https://doi.org/10.1002/ccs3.70091","url":null,"abstract":"<p>This study investigated the pathological relevance of the serine palmitoyltransferase long chain base subunit 2 (Sptlc2)–ceramide axis in nonobese nonalcoholic fatty liver disease (NAFLD), focusing on hepatic steatosis, inflammation, oxidative stress, and mitochondrial dysfunction. A nonobese NAFLD rat model was established using a high-temperature dry-fried soybean diet. Integrated liquid chromatography-mass spectrometry-based proteomic and metabolomic analyses were used to identify candidate pathways. Sptlc2 function was validated by AAV2/8-mediated liver-directed knockdown in vivo, lentiviral knockdown in primary hepatocytes, and C2-ceramide rescue experiments. Multi-omics profiling identified Sptlc2 as a sphingolipid metabolism-related candidate in the model. Sptlc2 knockdown reduced long-chain ceramide accumulation, hepatic lipid deposition, inflammatory cytokine expression, oxidative stress, and hepatocyte injury. In primary hepatocytes, Sptlc2 silencing improved mitochondrial respiration, membrane potential, calcium and reactive oxygen species homeostasis, and mitochondrial ultrastructure. These protective effects were partially reversed by C2-ceramide in vitro and in vivo. The Sptlc2–ceramide axis contributes to ceramide accumulation, hepatic lipotoxicity, inflammatory activation, and mitochondrial dysfunction in this nonobese NAFLD model, suggesting its potential relevance as a therapeutic target for further investigation.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"20 2","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccs3.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}