LncRNA SNHG5 promotes macrophage lipid accumulation and aggravates atherosclerosis by targeting the...

Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) has been implicated in cell death, glucose homeostasis, and tumor progression, yet its role in atherosclerosis (AS) remains unclear. In this study, SNHG5 expression was markedly elevated in aortic tissues of high-fat diet-fed apoE^-/- mice and in ox-LDL-stimulated THP-1 macrophages. Lentiviral-mediated SNHG5 silencing in vivo reduced plaque burden, attenuated lipid deposition, increased collagen content, and decreased systemic inflammation. Moreover, SNHG5 knockdown increased plasma HDL-C and promoted reverse cholesterol transport. In mouse peritoneal macrophages and THP-1-derived foam cells, SNHG5 silencing enhanced cholesterol efflux to lipid-free apoA-I without affecting uptake, accompanied by upregulation of ABCA1. LXRα expression remained unchanged, whereas HDAC3 was downregulated; HDAC3 overexpression reversed the effects of SNHG5 knockdown on ABCA1 expression, cholesterol efflux, and foam cell formation. Subcellular fractionation indicated cytoplasmic localization of SNHG5, and luciferase reporter and RNA pull-down assays confirmed that it functions as a competing endogenous RNA for miR-216a-5p. Inhibition of miR-216a-5p largely abolished the effects of SNHG5 silencing, establishing the SNHG5/miR-216a-5p/HDAC3 axis as a key regulator of macrophage lipid handling. Collectively, these findings demonstrate that SNHG5 promotes macrophage lipid accumulation and atherogenesis by sequestering miR-216a-5p to upregulate HDAC3 and suppress ABCA1-mediated cholesterol efflux, highlighting SNHG5 as a potential therapeutic target for AS.