Introduction The rising prevalence of metabolic-associated fatty liver disease (MAFLD) poses a serious public health threat, while long non-coding RNAs, key regulators of hepatic lipid metabolism, are closely linked to its development and progression. This study identified a novel MAFLD-associated antisense lncRNA, lnc-CidecAS , aiming to characterize its molecular structure and elucidate its regulatory role in hepatic lipid metabolism. Methods The sequence characteristics and coding potential of lnc-CidecAS were determined using RACE technology and flag-tagged expression vectors. Overexpression in AML12 hepatocytes was conducted to assess its effects on lipid metabolism-related genes and extracellular triglyceride (TG) levels. Both aged mice and HFD-induced obesity models were utilized for in vivo validation. Physiological parameters from blood, liver, and muscle tissues were measured after adeno-associated virus-mediated delivery of lnc-CidecAS to evaluate systemic lipid metabolism. Mechanistically, ChIRP-MS was employed to identify lnc-CidecAS interacting proteins, and the functional interaction with ATP1a1 was confirmed through siRNA knockdown and enzymatic activity assays. Results Inc-CidecAS was primarily localized in the cytoplasm. Its overexpression in AML12 cells significantly reduced extracellular TG levels while upregulated key lipid metabolism genes ( AMPK , ATGL , HSL , CPT1 and ACOX1 ). In vivo , lnc-CidecAS expression decreased under fasting conditions, declined with age, and showed a negative correlation with blood lipid levels. Overexpression of lnc-CidecAS reduced body fat and serum lipid concentrations in mice. In this HFD-induced obesity model, hepatic-specific overexpression of lnc-CidecAS markedly alleviated fat deposition in the liver and muscle, concurrently lowering serum TG and total cholesterol. Mechanistic studies revealed that lnc-CidecAS binds to ATP1a1, enhancing its gene expression and enzymatic activity, thereby promoting lipid metabolism. Discussion Our study reveals the regulatory role of lnc-CidecAS in hepatocyte lipid metabolism, and reveals its molecular mechanism via interaction with ATP1a1, identifying a novel lnc-CidecAS –ATP1a1 regulatory axis. This discovery expands our understanding of how lncRNAs cooperate with proteins to regulate cellular metabolism. Consequently, targeting this pathway provides a theoretical foundation for developing precise therapies against MAFLD and related metabolic disorders.
Yu et al. (2026) studied this question.