8-Chloroadenosine suppresses hepatocellular carcinoma progression via ADAR1/PPARγ axis-mediated lipid metabolism

The invasive and metastatic potential of hepatocellular carcinoma (HCC) is tightly linked to lipid metabolic reprogramming. However, existing knowledge of the molecular regulatory network governing lipid metabolism in HCC remains incomplete. This study reveals for the first time that ADAR1 promotes HCC progression via direct binding to PPARγ mRNA to regulate lipid metabolism. Through multi-omics approaches (publicly available single-cell sequencing databases, clinical sample analysis, and cellular models), we showed that ADAR1 was aberrantly up-regulated in HCC and promoted tumor cell proliferation, migration, and invasion. The adenosine analog 8-chloroadenosine (8-Cl-Ado) dose- and time-dependently down-regulated ADAR1 expression. Transcriptomic analysis revealed that 8-Cl-Ado significantly suppressed key genes associated with cholesterol synthesis and fatty acid metabolism. Mechanistically, ADAR1 binds to PPARγ mRNA, thereby activating the PPAR signaling axis, while PPARγ knockdown significantly abrogates malignant phenotypes in HCC. Functional rescue experiments confirmed that overexpression of the ADAR1 p150 isoform rescued the tumor-suppressive phenotype induced by 8-Cl-Ado. Collectively, these findings demonstrate that 8-Cl-Ado inhibits hepatocarcinogenesis and progression by suppressing ADAR1 and subsequently regulating PPARγ-mediated lipid metabolic processes, providing novel therapeutic targets and potential intervention strategies for HCC.