Competitive adsorption of microRNA-532-3p by circular RNA SOD2 activates Thioredoxin Interacting Protein/NLR family pyrin domain containing 3 pathway and promotes pyroptosis of non-alcoholic fatty hepatocytes

Chen, Fengjuan1; Xing, Yufeng2; Chen, Zhijie1; Chen, Xiaoman3; Li, Jie1; Gong, Si1; Luo, Fang1; Cai, Qingxian1

2024-04-24

10.1186/s40001-024-01817-4

EUROPEAN JOURNAL OF MEDICAL RESEARCH   影响因子和分区

0949-2321

2047-783X

Objective There is a growing body of evidence indicating that pyroptosis, a programmed cell death mechanism, plays a crucial role in the exacerbation of inflammation and fibrosis in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Circular RNAs (circRNAs), functioning as vital regulators within NAFLD, have been shown to mediate the process of cell pyroptosis. This study aims to elucidate the roles and mechanisms of circRNAs in NAFLD.Methods Utilizing a high-fat diet (HFD)-induced rat model for in vivo experimentation and hepatocytes treated with palmitic acid (PA) for in vitro models, we identified circular RNA SOD2 (circSOD2) as our circRNA of interest through analysis with the circMine database. The expression levels of associated genes and pyroptosis-related proteins were determined using quantitative real-time polymerase chain reaction and Western blotting, alongside immunohistochemistry. Serum liver function markers, cellular inflammatory cytokines, malondialdehyde, lactate dehydrogenase levels, and mitochondrial membrane potential, were assessed using enzyme-linked immunosorbent assay, standard assay kits, or JC-1 staining. Flow cytometry was employed to detect pyroptotic cells, and lipid deposition in liver tissues was observed via Oil Red O staining. The interactions between miR-532-3p/circSOD2 and miR-532-3p/Thioredoxin Interacting Protein (TXNIP) were validated through dual-luciferase reporter assays and RNA immunoprecipitation experiments.Results Our findings demonstrate that, in both in vivo and in vitro NAFLD models, there was an upregulation of circSOD2 and TXNIP, alongside a downregulation of miR-532-3p. Mechanistically, miR-532-3p directly bound to the 3'-UTR of TXNIP, thereby mediating inflammation and cell pyroptosis through targeting the TXNIP/NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathway. circSOD2 directly interacted with miR-532-3p, relieving the suppression on the TXNIP/NLRP3 signaling pathway. Functionally, the knockdown of circSOD2 or TXNIP improved hepatocyte pyroptosis; the deletion of miR-532-3p reversed the effects of circSOD2 knockdown, and the deletion of TXNIP reversed the effects of circSOD2 overexpression. Furthermore, the knockdown of circSOD2 significantly mitigated the progression of NAFLD in vivo.Conclusion circSOD2 competitively sponges miR-532-3p to activate the TXNIP/NLRP3 inflammasome signaling pathway, promoting pyroptosis in NAFLD.

Circular RNA SOD2 MicroRNA-532-3p Non-alcoholic fatty liver disease Pyroptosis

SCI

英语

第一 ; 通讯

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:001207769000001

BMC

CLINICAL MEDICINE

Web of Science

1.Southern Univ Sci & Technol, Peoples Hosp Shenzhen 3, Affiliated Hosp 2, Dept Hepatopathy, 29 Bulan Rd, Shenzhen 518112, Guangdong, Peoples R China
2.Shenzhen Tradit Chinese Med Hosp, Dept Hepatopathy, Shenzhen 518033, Guangdong, Peoples R China
3.Sun Yat Sen Univ, Affiliated Hosp 3, Dept Infect Dis, Guangzhou 510630, Guangdong, Peoples R China

Chen, Fengjuan,Xing, Yufeng,Chen, Zhijie,et al. Competitive adsorption of microRNA-532-3p by circular RNA SOD2 activates Thioredoxin Interacting Protein/NLR family pyrin domain containing 3 pathway and promotes pyroptosis of non-alcoholic fatty hepatocytes[J]. EUROPEAN JOURNAL OF MEDICAL RESEARCH,2024,29(1).

Chen, Fengjuan.,Xing, Yufeng.,Chen, Zhijie.,Chen, Xiaoman.,Li, Jie.,...&Cai, Qingxian.(2024).Competitive adsorption of microRNA-532-3p by circular RNA SOD2 activates Thioredoxin Interacting Protein/NLR family pyrin domain containing 3 pathway and promotes pyroptosis of non-alcoholic fatty hepatocytes.EUROPEAN JOURNAL OF MEDICAL RESEARCH,29(1).

Chen, Fengjuan,et al."Competitive adsorption of microRNA-532-3p by circular RNA SOD2 activates Thioredoxin Interacting Protein/NLR family pyrin domain containing 3 pathway and promotes pyroptosis of non-alcoholic fatty hepatocytes".EUROPEAN JOURNAL OF MEDICAL RESEARCH 29.1(2024).