Squid-derived protamine: A natural basic protein and its PEGylated derivative as anti-cancer agents in hepatocellular carcinoma.

Protamine is a naturally occurring cationic protein derived from marine organisms. Due to its unique protective and self-repairing properties, it has attracted significant attention in the biomedical field. This study investigates the anticancer effects of SOP and its PEGylated derivative (SOP-PEG) in hepatocellular carcinoma (HCC). Both SOP and SOP-PEG demonstrated significant tumor growth inhibition in both in vitro and in vivo experiments, with no apparent toxicity observed. Mechanistically, SOP and SOP-PEG induce the generation of reactive oxygen species (ROS), which activate the P53-mediated mitochondrial apoptosis pathway, thereby promoting apoptosis in Hepa1-6 cells. Furthermore, SOP and SOP-PEG downregulate the expression of CDK1, leading to G2/M phase cell cycle arrest, inhibition of the PI3K-Akt signaling pathway, and further amplification of apoptotic signaling. Notably, PEGylation significantly improves the pharmacokinetic properties and targeting ability of SOP, thereby enhancing its therapeutic efficacy. Moreover, CDK1 knockdown further potentiates the G2/M phase arrest and apoptosis induced by SOP and SOP-PEG. In summary, this study reveals the potential of SOP and SOP-PEG as marine-derived biological macromolecules with potent anti-HCC activity and establishes the critical regulatory role of CDK1 within the CDK1/PI3K/Akt signaling pathway. Targeting this pathway could offer novel strategies for HCC treatment. These findings suggest that SOP and SOP-PEG are promising candidates for HCC therapy and support CDK1 inhibition as a potential therapeutic strategy. This study provides new biomacromolecular candidates for HCC treatment and offers significant theoretical insights for future drug development and targeted therapeutic strategies.