CircZBTB46 alleviates metabolic dysfunction–associated steatotic liver disease by targeting miRNA-326/FGF1 axis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide, characterized by multiple metabolic disturbances. This complexity poses significant challenges for early diagnosis and effective treatment, highlighting the urgent need for novel biomarkers and therapeutic strategies. Circular RNAs (circRNAs) have attracted attention due to their unique stability and regulatory roles in various diseases, providing new opportunities for MASLD diagnosis and treatment. This study investigated the role of circZBTB46 in MASLD and its underlying molecular mechanism. Liver tissues from three healthy controls, three patients with MASLD, and three patients with metabolic dysfunction-associated steatohepatitis (MASH) were analyzed using RNA sequencing and bioinformatics analysis to identify differentially expressed circRNAs. CircRNA-miRNA interactions were predicted through the circinteractome database and validated by dual-luciferase reporter gene assays and RNA pull-down experiments. mRNA and protein expression were evaluated by qRT-PCR and western blot, while triglyceride and cholesterol levels were measured by ELISA. Lipid deposition was visualized through Oil Red O and BODIPY 493/503 staining. The results showed that circZBTB46, derived from the ZBTB46 gene, was downregulated in patients with MASLD and in experimental models. Overexpression of circZBTB46 significantly reduced hepatic lipid accumulation and triglyceride content. This effect is mediated through the circZBTB46/miRNA-326/FGF1 pathway, in which circZBTB46 directly binds to miRNA-326, functioning as a competitive endogenous RNA (ceRNA) to relieve miRNA-326-mediated suppression of FGF1, thereby alleviating hepatic lipid accumulation. These findings reveal the critical role of circZBTB46 in MASLD and provide valuable insights into its potential as a diagnostic biomarker and therapeutic target for MASLD.