Ultrasound-responsive nanobubble-mediated sonodynamic therapy sensitizes disulfidptosis in the treatment of liver hepatocellular carcinoma.

Disulfidptosis, a newly identified regulated cell death, is linked to tumor progression, particularly in cancers with elevated SLC7A11 expression. This study investigates SLC7A11 expression in liver hepatocellular carcinoma (LIHC) and evaluates the therapeutic potential of ICG@C3F8-KL nanobubbles (NBs) combined with sonodynamic therapy (SDT) for inducing disulfidptosis. Bioinformatics analysis of TCGA datasets revealed upregulation of SLC7A11 in LIHC tissues. The synthesized ICG@C3F8-KL NBs exhibited a mean diameter of 156.46 nm and stable properties, with high encapsulation efficiencies of 51.32 % ± 0.7 % for KL and 80.15 % ± 0.21 % for ICG. In vitro, ICG@C3F8-KL NBs, under ultrasound, generated reactive oxygen species (ROS), enhancing cytotoxicity in HepG2 cells with an IC50 lower than KL alone. These NBs also inhibited cell migration and colony formation, suggesting disulfidptosis induction via altered glucose uptake and NADP+/NADPH ratio, as well as F-actin contraction. In vivo, ICG@C3F8-KL NBs accumulated in tumor tissues and suppressed growth without significant toxicity. Unsupervised clustering of disulfidptosis-related genes in TCGA LIHC cohort identified subtypes with distinct prognoses, and a predictive model based on five key genes was developed. In conclusion, ICG@C3F8-KL NBs, combined with ultrasound, effectively induce disulfidptosis, offering a promising strategy for LIHC treatment, with the potential for personalized therapy informed by disulfide-associated gene signatures.