m ⁶ A‐Modified circRAPGEF1 Interaction with IGF2BP3 Promotes Hepatocellular Carcinoma Progression via Reprogramming Aspartate Metabolism

Abstract Hepatocellular carcinoma (HCC) progression and therapy sensitivity are critically fueled by liver cancer stem cells (LCSCs), yet the regulatory mechanisms of circular RNAs (circRNAs) on LCSCs remain elusive. Here, through circRNA microarray analysis of LCSCs and non‐stem HCC cells, circRAPGEF1 is identified as a LCSC‐enriched circRNA upregulated in HCC tissues and predictive of poor patient survival. Functionally, circRAPGEF1 promoted the stemness properties, proliferation, and tumorigenicity of HCC cells. Mechanistically, the METTL3‐mediated N ⁶ ‐methyladenosine (m ⁶ A) modification of circRAPGEF1 facilitated KH domain‐dependent binding of IGF2BP3 to its UGGAC motif, which conferring stability to circRAPGEF1 while competitively disrupting the IGF2BP3/ ASS1 mRNA interaction. This process led to the degradation of ASS1 mRNA, triggering aspartate accumulation and activation of the S6K/CAD signaling pathway. Crucially, circRAPGEF1 overexpression reduced the sorafenib sensitivity, whereas targeting circRAPGEF1 using nanoparticles‐mediated systematic siRNAs delivery effectively sensitized HCC cells to sorafenib. Collectively, these findings unveil a METTL3/circRAPGEF1/IGF2BP3/ASS1 regulatory axis that drives aspartate metabolic reprogramming to fuel HCC stemness properties, positioning circRAPGEF1 as a dual prognostic biomarker and therapeutic target to enhance sorafenib efficacy in HCC.