Background <p>Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related mortality globally. It is urgently necessary to elucidate the pathogenesis of HCC and develop novel therapeutic strategies. Although certain circular RNAs (circRNAs) act as oncogenic drivers in HCC progression, the underlying mechanisms remain poorly understood.</p> Methods <p>CircRNA-miRNA-mRNA network was established to screen potential circRNAs that were associated with HCC progression. CCK8, colony formation, EdU staining, wound healing, transwell assay and xenograft models were implemented to investigate the role of circRPPH1 in HCC progression. RNA-seq, luciferase reporter assays, Turbo-ID, mass spectrometry, co-immunoprecipitation and RNA-binding protein immunoprecipitation assays and rescue experiments were employed to determine the underlying molecular mechanism.</p> Results <p>CircRPPH1 was significantly upregulated in HCC tissues and it promoted HCC progression both in vitro and in vivo. The elevated circRPPH1 expression in HCC was due to its increased stability, which was mediated by m⁶A methylation. CircRPPH1 could suppress the level of PPARα to promote HCC progression. Mechanistically, we found that circRPPH1 sponged miR-7845-5p to upregulate the expression of SOX4, which inhibited the transcription of PPARα. CircRPPH1 could also competitively bind with USP1, resulting in increased ubiquitination and degradation of PPARα. We also demonstrated that circRPPH1-ASOs could effectively inhibit HCC growth in vivo.</p> Conclusions <p>CircRPPH1 is a tumor-promoting circRNA, which inhibits PPARα transcription through miR-7845-5p/SOX4 axis and accelerates its ubiquitination and degradation through competitively binding with USP1. These findings suggest that circRPPH1 may serve as a promising therapeutic target for HCC treatment.</p>