The classical accelerated blood clearance (ABC) phenomenon induced by polyethylene glycol-modified liposomes (PEG-Lip) consists of "induction phase" and "effectuation phase." Despite extensive research on the ABC phenomenon, researchers still have limited knowledge of it. Our recent research showed that the hepatic accumulation of PEG-Lip was rapidly reduced after the ABC phenomenon "effectuation phase" and proved the roles of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in this process. However, our understanding of the underlying mechanisms of hepatic accumulation change remains incomplete. Our further research found that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway was also significantly upregulated in the ABC phenomenon. Therefore, this study aimed to systemically investigate the intrahepatic disposition fate of repeated injections of PEG-Lip and explore the mechanisms of accelerated hepatic clearance from the perspective of the PI3K-AKT signaling pathway and its regulated transporters. Our results indicated that after repeated injections, the hepatic accumulation of PEG-Lip significantly increased within 1-4 hours (the "effectuation phase") and then significantly decreased during 8-24 hours, which we defined as the "regression phase." Mechanistic studies showed that repeated injections of PEG-Lip could activate the PI3K-AKT signaling pathway, which accelerated the hepatic clearance of encapsulated docetaxel by upregulating P-gp and Mrp2, thereby inducing the ABC phenomenon "regression phase." This study reveals the dynamic changes in hepatic accumulation of PEGylated liposomal docetaxel after repeated injections and demonstrates the important role of the PI3K-AKT-P-gp/Mrp2 signaling pathway in the ABC phenomenon "regression phase," providing a theoretical basis for the discovery of novel therapeutic targets. SIGNIFICANCE STATEMENT: This study reveals the bidirectional dynamic changes in hepatic accumulation of PEGylated liposomal docetaxel and innovatively proposes the concept of ABC phenomenon "regression phase", advancing the understanding for the developmental process of the ABC phenomenon. This study identifies the PI3K-AKT-P-gp/Mrp2 signaling pathway as a critical molecular regulator of accelerated hepatic clearance of PEGylated liposomal docetaxel and offers a therapeutic strategy to mitigate this phase through targeted inhibition of the PI3K-AKT-P-gp/Mrp2 signaling pathway.