The findings from both laboratory and animal trials suggest that HCC-targeted exosomes (ExoSP94-Lamp2b-RRM) can deliver multiple siRNAs to HCC tissues, boost sorafenib-induced ferroptosis by suppressing GPX4 and DHODH expression, and thereby improve HCC responsiveness to sorafenib, offering a new approach to address sorafenib resistance through the lens of ferroptosis. Here, GPX4 is linked to hepatocellular carcinoma.