Nitroxoline upregulates low-density lipoprotein receptors expression, enhances lipid metabolism, and reduces hepatic steatosis and atherosclerosis in Apoe−/− mice

Low-density lipoprotein receptors (LDLRs) play a critical role in maintaining cholesterol homeostasis. Dysregulation of lipid metabolism contributes to atherosclerosis and steatohepatitis. This study investigated the effects of nitroxoline on LDLR expression and its protective role in lipid dysregulation, hepatic steatosis, and atherosclerosis. Through comprehensive screening of FDA-approved clinical drugs, nitroxoline was identified as a promising candidate for modulating LDLR. Functional validation in Huh7 cells using quantitative reverse transcription polymerase chain reaction, western blotting, flow cytometry, and RNA-seq analysis showed that nitroxoline significantly upregulated LDLR mRNA and protein expression, enhancing LDL uptake and binding capacity. Mechanistically, nitroxoline promoted SREBF2 expression via PPP2CA suppression and stabilized LDLR mRNA through AMPK- and JNK-dependent repression of the RNA-binding proteins, notably HNRNPD. Transcriptomic profiling revealed increased expression of genes related to cholesterol homeostasis and decreased expression of genes involved in triglyceride biosynthesis, including GPAT, AGPAT, and PNPLA3. In Apoe^−/− mice, nitroxoline reduced serum levels of total cholesterol, triglycerides, and LDL-C without affecting HDLC. Histological analyses demonstrated significant reductions in hepatic steatosis, fibrosis, and stellate cell activation, along with a modest attenuation of atherosclerotic plaque formation in the aortic root. These molecular and phenotypic effects were consistent with improved lipid clearance and hepatocellular protection. These findings suggest that nitroxoline exerts dual actions by upregulating LDLR expression and improving hepatic lipid metabolism. Given its established clinical safety and oral bioavailability, nitroxoline may offer repurposing potential as a therapeutic agent for treating lipid-related metabolic disorders and preventing atherosclerotic cardiovascular disease.