Through systematic evaluation of Alisertib/Donafenib combinatorial treatment in HCC models, we establish optimized therapeutic thresholds (alisertib: 2.5 μM in vitro; 30 mg/kg in vivo) that augment Donafenib’s ferroptotic efficacy via NF-κB/NRF2 axis suppression. Here, NFKB1 is linked to hepatocellular carcinoma.