LncRNA MIR17HG accelerates the development of atherosclerosis by promoting macrophage pyroptosis through the miR-301a-3p/TXNIP pathway.

Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation, immune dysregulation, and cell death within the arterial wall. While extensive research has been devoted to the understanding of its molecular pathogenesis, novel regulatory factors contributing to its progression remain to be identified. Macrophage pyroptosis and the subsequent inflammatory response play a central role in atherogenesis. Recent evidence has implicated long non-coding RNAs (lncRNAs) in macrophage dysfunction and vascular inflammation; however, the precise roles of specific lncRNAs in pyroptosis-mediated atherogenesis are still unclear. In this study, we identified lncRNA MIR17HG as a potential regulator of macrophage pyroptosis and atherosclerosis progression. Exposure of THP-1-derived macrophages to ox-LDL induced a dose-dependent increase in MIR17HG expression. Silencing of MIR17HG significantly reduced the expression of pyroptosis-related factors, caspase-1 activity, LDH release, proinflammatory cytokine secretion, and plasma membrane disruption in ox-LDL-treated macrophages, indicating attenuation of pyroptosis. These effects were reversed by TXNIP overexpression or transfection with a miR-301a-3p inhibitor. Mechanistically, MIR17HG functioned as a competing endogenous RNA (ceRNA), sponging miR-301a-3p to upregulate TXNIP expression and activate the NLRP3 inflammasome. Consistently, MIR17HG knockdown reduced plaque burden, improved plasma lipid profile, and alleviated inflammation in high-fat diet-fed apoE mice; these protective effects were abrogated by administration of a miR-301a-3p antagomir. Collectively, our findings reveal that MIR17HG promotes atherosclerosis by enhancing macrophage pyroptosis through the miR-301a-3p/TXNIP/NLRP3 axis, offering new insight into the lncRNA-mediated regulation of vascular inflammation and plaque development.