A highly biocompatible self-assembled Pt(IV) nanoplatform integrating Nrf2 inhibition for synergistic apoptosis and ferroptosis in hepatocellular carcinoma

The clinical efficacy of cisplatin (CDDP), a first-line chemotherapeutic agent for hepatocellular carcinoma (HCC), is limited by dose-limiting systemic toxicity and intrinsic or acquired resistance. To address these drawbacks, self-assembled Pt(IV) prodrug nanoparticles, termed DGA NPs, were constructed via conjugation of CDDP with 18β-glycyrrhetinic acid (GA). In vitro, DGA NPs demonstrated superior antiproliferative activity over CDDP against a range of cancer cell lines, including a CDDP-resistant model. Furthermore, they effectively inhibited the migration and invasion of HepG2 cells. Mechanistically, DGA NPs induced DNA damage, mitochondrial dysfunction, and reactive oxygen species (ROS) accumulation. These cellular stresses led to the sustained activation of the p53 and AMPK pathways, thereby driving robust apoptosis. Notably, through inhibiting the Nrf2 antioxidant axis, DGA NPs suppressed the PI3K/AKT/mTOR survival pathway and triggered ferroptosis in HCC cells. In a HepG2 xenograft model, DGA NPs demonstrated significantly superior antitumor efficacy relative to CDDP monotherapy or a CDDP/GA combination, without inducing detectable systemic toxicity. Collectively, DGA NPs represent an innovative Pt(IV)–based nanoplatform that simultaneously activates both apoptotic and ferroptosis pathways, offering a promising dual-mechanism strategy for the treatment of HCC. A novel Pt(IV) nanoplatform integrating cisplatin and 18β-GA induces dual apoptosis and ferroptosis by disrupting redox and survival signaling, thus overcoming cisplatin resistance and minimizing systemic toxicity in HCC.