scholarly journals YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes

2021 ◽  
Vol 22 (13) ◽  
pp. 6649
Author(s):  
Yunan Gao ◽  
Yan Sun ◽  
Adife Gulhan Ercan-Sencicek ◽  
Justin S. King ◽  
Brynn N. Akerberg ◽  
...  
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Heart Diseases ◽  
Luciferase Reporter ◽  
Binding Motif ◽  
Expression Levels ◽  
Genomic Regions

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.

scholarly journals miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Chenguang Ding ◽  
Xiaoming Ding ◽  
Jin Zheng ◽  
Bo Wang ◽  
Yang Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Renal Tubular Cell ◽  
In Cells

Abstract Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

scholarly journals Up-Regulating Relaxin Expression by G-Quadruplex Interactive Ligand to Achieve Antifibrotic Action

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3692-3700 ◽  
Author(s):  
Hui-Ping Gu ◽  
Sen Lin ◽  
Ming Xu ◽  
Hai-Yi Yu ◽  
Xiao-Jun Du ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Gene Promoter ◽  
Binding Motif ◽  
Endogenous Expression ◽  
G Quadruplex

Myocardial fibrosis is a key pathological change in a variety of heart diseases contributing to the development of heart failure, arrhythmias, and sudden death. Recent studies have shown that relaxin prevents and reverses cardiac fibrosis. Endogenous expression of relaxin was elevated in the setting of heart disease; the extent of such up-regulation, however, is insufficient to exert compensatory actions, and the mechanism regulating relaxin expression is poorly defined. In the rat relaxin-1 (RLN1, Chr1) gene promoter region we found presence of repeated guanine (G)-rich sequences, which allowed formation and stabilization of G-quadruplexes with the addition of a G-quadruplex interactive ligand berberine. The G-rich sequences and the G-quadruplexes were localized adjacent to the binding motif of signal transducer and activator of transcription (STAT)3, which negatively regulates relaxin expression. Thus, we hypothesized that the formation and stabilization of G-quadruplexes by berberine could influence relaxin expression. We found that berberine-induced formation of G-quadruplexes did increase relaxin gene expression measured at mRNA and protein levels. Formation of G-quadruplexes significantly reduced STAT3 binding to the promoter of relaxin gene. This was associated with consequent increase in the binding of RNA polymerase II and STAT5a to relaxin gene promoter. In cardiac fibroblasts and rats treated with angiotensin II, berberine was found to suppress fibroblast activation, collagen synthesis, and extent of cardiac fibrosis through up-regulating relaxin. The antifibrotic action of berberine in vitro and in vivo was similar to that by exogenous relaxin. Our findings document a novel therapeutic strategy for fibrosis through up-regulating expression of endogenous relaxin.

scholarly journals Therapeutic modulation of RNA-binding protein Rbm38 facilitates re-endothelialization after arterial injury

2019 ◽  
Vol 115 (12) ◽  
pp. 1804-1810 ◽  
Author(s):  
Kristina Sonnenschein ◽  
Jan Fiedler ◽  
Angelika Pfanne ◽  
Annette Just ◽  
Saskia Mitzka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Balloon Angioplasty ◽  
Carotid Arteries ◽  
Rna Binding ◽  
Luciferase Reporter ◽  
Binding Motif ◽  
Cell Functions ◽  
Endothelial Regeneration

Abstract Aims Delayed re-endothelialization after balloon angioplasty in patients with coronary or peripheral artery disease impairs vascular healing and leads to neointimal proliferation. In the present study, we examined the effect of RNA-binding motif protein 38 (Rbm38) during re-endothelialization in a murine model of experimental vascular injury. Methods and results Left common carotid arteries of C57BL/6 mice were electrically denudated and endothelial regeneration was evaluated. Profiling of RNA-binding proteins revealed dysregulated expression of Rbm38 in the denudated and regenerated areas. We next tested the importance of Rbm38 in human umbilical vein endothelial cells (HUVECS) and analysed its effects on cellular proliferation, migration and apoptosis. Rbm38 silencing in vitro demonstrated important beneficial functional effects on migratory capacity and proliferation of endothelial cells. In vivo, local silencing of Rbm38 also improved re-endothelialization of denuded carotid arteries. Luciferase reporter assay identified miR-98 and let-7f to regulate Rbm38 and the positive proliferative properties of Rbm38 silencing in vitro and in vivo were mimicked by therapeutic overexpression of these miRNAs. Conclusion The present data identified Rbm38 as an important factor of the regulation of various endothelial cell functions. Local inhibition of Rbm38 as well as overexpression of the upstream regulators miR-98 and let-7f improved endothelial regeneration in vivo and thus may be a novel therapeutic entry point to avoid endothelial damage after balloon angioplasty.

scholarly journals Cyclin D3-CDK6 Complex Facilitates Tumorigenesis by Regulating the C-Myc/miR-15a/16 Axis in a Feedback Loop in Gastric Cancer

2020 ◽  
Author(s):  
Yeting Hong ◽  
Wei He ◽  
Jianbin Zhang ◽  
Lu Shen ◽  
Chong Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Feedback Loop ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cyclin D3 ◽  
Luciferase Reporter

Abstract Background: Cyclin D3-CDK6 complex is a component of the core cell cycle machinery that regulates cell proliferation. By using Human Protein Atlas database, a higher expression level of this complex was found in gastric cancer. However, the function of this complex in gastric cancer remain poorly understood. This study aims to determine the expression pattern of this complex in gastric cancer and to investigate its biological role during tumorigenesis.Methods: To demonstrate that Cyclin D3-CDK6 regulate the c-Myc/miR-15a/16 axis in a feedback loop in gastric cancer, a series of methods were conducted both in vitro and in vivo experiments, including qRT-PCR, western blot analysis, EdU assay, flow cytometry, luciferase reporter assay and immunohistochemical staining. SPSS and Graphpad prism software were used for data analysis.Results: In this study, we found that Cyclin D3 and CDK6 were significantly upregulated in gastric cancer and correlated with poorer overall survival. Further study proved that this complex significantly promoted cell proliferation and cell cycle progression in vitro and accelerated xenografted tumor growth in vivo. Furthermore, we explored the molecular mechanisms through which the complex mediated Rb phosphorylation and then promoted c-Myc expression in vitro, we also found c-Myc could suppress miR-15a/16 expression in gastric cancer cell. Finally, we found that miR-15a/16 can simultaneously regulate Cyclin D3 and CDK6 expression as direct target genes.Conclusions: Our findings uncover the Cyclin D3-CDK6/c-Myc/miR-15a/16 feedback loop axis as a pivotal role in the regulation of gastric cancer tumorigenesis, and this regulating axis may provide a potential therapeutic target for gastric cancer treatment.

scholarly journals MAZ-LINC00645-GP73 Axis Promotes Hepatocellular Carcinoma Proliferation and Metastasis

2020 ◽  
Author(s):  
Yang Chen ◽  
Huiyan Li ◽  
Chunxun Liu ◽  
Yongmei Han ◽  
Yubao Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Tumor Promoter ◽  
Transcriptional Analysis ◽  
Luciferase Reporter ◽  
Chip Assay ◽  
Bioinformatics Analyses

Abstract BACKGROUND: Long non-coding RNAs (lncRNA) have been shown to play important roles in the development and progression of hepatocellular carcinoma (HCC). In this report, we examined the role of lncRNA LINC00645 in HCC. MATERIAL AND METHODS: Based on public databases and integrating bioinformatics analyses, the over-expression of LINC00645 in HCC tissues was detected and further validated in a cohort of liver tissues. A series of in vitro and in vivo functional experiments were executed to investigate the role of LINC00645 in the carcinogenesis and development of HCC. Comprehensive transcriptional analysis, chromatin immunoprecipitation (ChIP) assay, dual-luciferase reporter assay and western blot etc. were performed to explore the molecular mechanisms underlying the functions of LINC00645. RESULTS: LINC00645 was significantly upregulated in HCC cell lines and HCC tissues, which was correlated with poor prognosis in HCC patients. LINC00645 knockdown remarkably suppressed tumor growth in vitro and in vivo. Mechanistically, LINC00645 could competitively bind with miR-141-3p to prevent the degradation of its target gene GP73, which acts as a tumor-promoter in HCC. Furthermore, the ChIP assay showed that the transcription factor MAZ could bind to the LINC00645 promoter and increase its transcription. CONCLUSIONS: Collectively, this study demonstrated that LINC00645 plays a critical regulatory role in hepatocellular carcinoma cells and LINC00645 may serve as a potential diagnostic biomarker and therapeutic target of HCC. Thus, targeting MAZ/LINC00645/miR-141-3p/GP73 signaling axis may prevent the progression of HCC.

scholarly journals Targeting POLE2 Creates a Novel Vulnerability in Renal Cell Carcinoma via Modulating Stanniocalcin 1

2021 ◽  
Vol 9 ◽  
Author(s):  
Chuanjie Zhang ◽  
Yan Shen ◽  
Lili Gao ◽  
Xiaojing Wang ◽  
Da Huang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Western Blot ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Molecular Mechanisms ◽  
Cancer Genome ◽  
Clinicopathological Parameters ◽  
Expression Levels

ObjectiveThe aim of this study is to investigate the biological functions and the underlying mechanisms of DNA polymerase epsilon subunit 2 (POLE2) in renal cell carcinoma (RCC).MethodsThe datasets of POLE2 expression in The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) and International Cancer Genome Consortium (ICGC) databases was selected and the correlation between POLE2 and various clinicopathological parameters was analyzed. The POLE2 expression in RCC tissues was examined by immunohistochemistry. The POLE2 knockdown cell lines were constructed. In vitro and in vivo experiments were carried out to investigate the function of POLE2 on cellular biology of RCC, including cell viability assay, clone formation assay, flow cytometry, wound-healing assay, Transwell assay, qRT-PCR, Western blot, etc. Besides, microarray, co-immunoprecipitation, rescue experiment, and Western blot were used to investigate the molecular mechanisms underlying the functions of POLE2.ResultsPOLE2 was overexpressed in RCC tissues, and high expression of POLE2 was correlated with poor prognosis of RCC. Furthermore, knockdown of POLE2 significantly inhibited cell proliferation, migration, and facilitated apoptosis in vitro. In vivo experiments revealed that POLE2 attenuated RCC tumorigenesis and tumor growth. we also illuminated that stanniocalcin 1 (STC1) was a downstream gene of POLE2, which promoted the occurrence and development of RCC. Besides, knockdown of POLE2 significantly upregulated the expression levels of Bad and p21 while the expression levels of HSP70, IGF-I, IGF-II, survivin, and sTNF-R1 were significantly downregulated. Western blot analysis also showed that knockdown of POLE2 inhibited the expression levels of Cancer-related pathway proteins including p-Akt, CCND1, MAPK9, and PIK3CA.ConclusionKnockdown of POLE2 attenuates RCC cells proliferation and migration by regulating STC1, suggesting that POLE2-STC1 may become a potential target for RCC therapy.

scholarly journals MicroRNA-27a targets Sfrp1 to induce renal fibrosis in diabetic nephropathy by activating Wnt/β-Catenin signalling

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
MingJun Shi ◽  
PingPing Tian ◽  
ZhongQiang Liu ◽  
Fan Zhang ◽  
YingYing Zhang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Renal Fibrosis ◽  
Negative Control ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Expression Levels ◽  
Stage Renal Disease

Abstract Diabetic nephropathy (DN) commonly causes end-stage renal disease (ESRD). Increasing evidence indicates that abnormal miRNA expression is tightly associated with chronic kidney disease (CKD). This work aimed to investigate whether miR-27a can promote the occurrence of renal fibrosis in DN by suppressing the expression of secreted frizzled-related protein 1 (Sfrp1) to activate Wnt/β-catenin signalling. Therefore, we assessed the expression levels of miR-27a, Sfrp1, Wnt signalling components, and extracellular matrix (ECM)-related molecules in vitro and in vivo. Sfrp1 was significantly down-regulated in a high-glucose environment, while miR-27a levels were markedly increased. A luciferase reporter assay confirmed that miR-27a down-regulated Sfrp1 by binding to the 3′ untranslated region directly. Further, NRK-52E cells under high-glucose conditions underwent transfection with miR-27a mimic or the corresponding negative control, miR-27a inhibitor or the corresponding negative control, si-Sfrp1, or combined miR-27a inhibitor and si-Sfrp1. Immunoblotting and immunofluorescence were performed to assess the relative expression levels of Wnt/β-catenin signalling and ECM components. The mRNA levels of Sfrp1, miR-27a, and ECM-related molecules were also detected by quantitative real-time PCR (qPCR). We found that miR-27a inhibitor inactivated Wnt/β-catenin signalling and reduced ECM deposition. Conversely, Wnt/β-catenin signalling was activated, while ECM deposition was increased after transfection with si-Sfrp1. Interestingly, miR-27a inhibitor attenuated the effects of si-Sfrp1. We concluded that miR-27a down-regulated Sfrp1 and activated Wnt/β-catenin signalling to promote renal fibrosis.

scholarly journals EPC-Derived Exosomal miR-1246 and miR-1290 Regulate Phenotypic Changes of Fibroblasts to Endothelial Cells to Exert Protective Effects on Myocardial Infarction by Targeting ELF5 and SP1

2021 ◽  
Vol 9 ◽  
Author(s):  
Yulang Huang ◽  
Lifang Chen ◽  
Zongming Feng ◽  
Weixin Chen ◽  
Shaodi Yan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Cardiac Injury ◽  
Immunofluorescence Staining ◽  
Luciferase Reporter ◽  
Protective Effects ◽  
Expression Levels ◽  
Phenotypic Changes

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Endothelial progenitor cell (EPC)-derived exosomes have been found to be effective in alleviating MI, while the detailed mechanisms remain unclear. The present study aimed to determine the protective effects of EPC-derived exosomal miR-1246 and miR-1290 on MI-induced injury and to explore the underlying molecular mechanisms. The exosomes were extracted from EPCs; gene expression levels were determined by quantitative real-time PCR, and protein expression levels were determined by western blot and immunofluorescence staining, respectively. The angiogenesis and proliferation of human cardiac fibroblasts (HCFs) were determined by tube formation assay and immunofluorescence staining of PKH67, respectively. Luciferase reporter, CHIP, and EMSA assays determined the interaction between miR-1246/1290 and the targeted genes (EFL5 and SP1). The protective effects of miR-1246/1290 on MI were evaluated in a rat model of MI. EPC-derived exosomes significantly upregulated miR-1246 and miR-1290 expression and promoted phenotypic changes of fibroblasts to endothelial cells, angiogenesis, and proliferation in HCFs. Exosomes from EPCs with miR-1246 or miR-1290 mimics transfection promoted phenotypic changes of fibroblasts to endothelial cells and angiogenesis in HCFs, while exosomes from EPCs with miR-1246 or miR-1290 knockdown showed opposite effects in HCFs. Mechanistically, miR-1246 and miR-1290 from EPC-derived exosomes induced upregulation of ELF5 and SP1, respectively, by targeting the promoter regions of corresponding genes. Overexpression of both ELF5 and SP1 enhanced phenotypic changes of fibroblasts to endothelial cells and angiogenesis in HCFs pretreated with exosomes from EPCs with miR-1246 or miR-1290 mimics transfection, while knockdown of both EFL5 and SP1 exerted the opposite effects in HCFs. Both ELF5 and SP1 can bind to the promoter of CD31, leading to the upregulation of CD31 in HCFs. Furthermore, in vivo animal studies showed that exosomes from EPCs with miR-1246 or miR-1290 overexpression attenuated the MI-induced cardiac injury in the rats and caused an increase in ELF5, SP1, and CD31 expression, respectively, but suppressed α-SMA expression in the cardiac tissues. In conclusion, our study revealed that miR-1246 and miR-1290 in EPC-derived exosomes enhanced in vitro and in vivo angiogenesis in MI, and these improvements may be associated with amelioration of cardiac injury and cardiac fibrosis after MI.

scholarly journals CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 129
Author(s):  
Huinan Qu ◽  
Da Qi ◽  
Xinqi Wang ◽  
Yuan Dong ◽  
Qiu Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Suppressor Gene ◽  
Binding Motif ◽  
Cancer Proliferation ◽  
In Vivo Experiments

Claudin 6 (CLDN6) was found to be a breast cancer suppressor gene, which is lowly expressed in breast cancer and inhibits breast cancer cell proliferation upon overexpression. However, the mechanism by which CLDN6 inhibits breast cancer proliferation is unclear. Here, we investigated this issue and elucidated the molecular mechanisms by which CLDN6 inhibits breast cancer proliferation. First, we verified that CLDN6 was lowly expressed in breast cancer tissues and that patients with lower CLDN6 expression had a worse prognosis. Next, we confirmed that CLDN6 inhibited breast cancer proliferation through in vitro and in vivo experiments. As for the mechanism, we found that CLDN6 inhibited c–MYC–mediated aerobic glycolysis based on a metabolomic analysis of CLDN6 affecting cellular lactate levels. CLDN6 interacted with a transcriptional co–activator with PDZ-binding motif (TAZ) and reduced the level of TAZ, thereby suppressing c–MYC transcription, which led to a reduction in glucose uptake and lactate production. Considered together, our results suggested that CLDN6 suppressed c–MYC–mediated aerobic glycolysis to inhibit the proliferation of breast cancer by TAZ, which indicated that CLDN6 acted as a novel regulator of aerobic glycolysis and provided a theoretical basis for CLDN6 as a biomarker of progression in breast cancer.

scholarly journals Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Yuanjun Lu ◽  
Yau-Tuen Chan ◽  
Hor-Yue Tan ◽  
Cheng Zhang ◽  
Wei Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Bioinformatics Analyses ◽  
Sorafenib Treatment ◽  
Hcc Cells

Abstract Background Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. Methods The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. Results We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Conclusion Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.

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