Non-thermal plasma-treated melatonin inhibits the biological activity of HCC cells by increasing intracellular ROS levels and reducing RRM2 expression.

Non-thermal plasma (NTP) is thought to have a cytotoxic effect on tumor cells. Although its application in cancer therapy has shown considerable promise, the current understanding of its mechanism of action and cellular responses remains incomplete. Furthermore, the use of melatonin (MEL) as an adjuvant anticancer drug remains unexplored. In this study, we found that NTP assists MEL in promoting apoptosis, delaying cell cycle progression, and inhibiting cell invasion and migration in hepatocellular carcinoma (HCC) cells. This mechanism may be associated with the regulation of intracellular reactive oxygen species levels and ribonucleotide reductase regulatory subunit M2 expression. Our findings confirm the pharmacological role of MEL and the adjuvant value of NTP, emphasizing their potential in combination therapy for HCC. Our study may have important implications for the development of new approaches for HCC treatment.