Hsa_piR_016975 Is a Novel Target of Nanotherapy that Boosts Hepatoma Progression and Sorafenib Resistance by Abating Maspin/GPX4-Mediated Ferroptosis

PIWI-interacting RNAs (piRNAs) are known to be involved in germline development, but their potential mechanisms in carcinogenesis remain elusive. Herein, we investigated the roles of hsa_piR_016975, a novel piRNA, in hepatocellular carcinoma (HCC) progression and its therapeutic effects on drug resistance to sorafenib. The results disclosed that hsa_piR_016975 was highly expressed in HCC and promoted HCC growth, metastasis, epithelial mesenchymal transition (EMT) formation, and sorafenib resistance. Mechanistic research uncovered that hsa_piR_016975 could target inhibition of the expression of serpin family B member 5 (SERPINB5; also known as Maspin) while up-regulating glutathione peroxidase 4 (GPX4) expression, thereby attenuating the ferroptosis and resulting in HCC progression and drug resistance. Furthermore, a novel delivery system was constructed, which was encapsulated with sorafenib and hsa_piR_016975 inhibitor in the nanoparticles of polylactic-co-glycolic acid and subsequently coated with the HCC cell membrane (namely, in-016975/Sora@PLGA-CM). The nanocomposites could effectively reverse HCC progression and sorafenib resistance by inducing hsa_piR_016975/Maspin/gpx4 axis-mediated ferroptosis in both subcutaneous xenograft model and orthotopic transplantation model. Overall, this study illuminates the critical role and molecular mechanisms of hsa_piR_016975 in hepatocarcinogenesis and provides a promising piRNA-oriented nanodelivery strategy for overcoming sorafenib resistance in HCC.