Nanoformulated Diacerein Alleviates Hyperlipidemia via Gut Microbiota Modulation In Vivo

ABSTRACT Hyperlipidemia is a major risk factor for cardiovascular disease, and current therapies often present limitations in tolerability. Diacerein, an anti‐inflammatory drug, has shown potential lipid‐lowering effects, yet its unclear mechanism and poor solubility remain key barriers for its further application. Herein, we develop a carboxymethyl cellulose‐based nanoformulation of diacerein (Nano‐DIA) and evaluate its lipid‐lowering efficacy and potential mechanism thereof. Nano‐DIA is feasibly fabricated via a sonication‐based top‐down method, characterized by uniform particle size and enhanced dispersity. Despite the Nano‐DIA showed marginal effects in lowering the lipid accumulation in hepatocytes in vitro, in vivo administration of Nano‐DIA significantly reduces serum total cholesterol, triglycerides (TG), and low‐density lipoprotein cholesterol (LDL‐C) levels compared to control group. 16S rRNA gene sequencing reveals that Nano‐DIA treatment restores the abundance of beneficial taxa and alters key bacterial genera associated with lipid metabolism, such as reducing the Firmicutes / Bacteroidetes ratio upon high fat diet (HFD) induction. These findings suggest that Nano‐DIA exerts potent anti‐hyperlipidemic effects, at least in part, through modulation of gut microbiota composition and function, therefore highlighting an alternative strategy for managing lipid disorders.