<p>Hepatocellular carcinoma (HCC), an infamously incurable tumor, is extremely sensitive to ferroptosis, and its development is greatly aided by the glutathione (GSH) antioxidant defense system. We present a gelatin (GT)/hyaluronic acid (HA)-stabilized Copper (Cu) and Iron (Fe) nanoparticle (5CFGH NPs) for HCC therapy that uses a self-amplified dual mechanism of cuproptosis and ferroptosis. It has a Cu/Fe mass ratio of 5:5. HA in 5CFGH selectively binds to HCC cells overexpressing CD44 receptor. This enables 5CFGH to release metal ions in acidic conditions after entering cells through receptor-mediated endocytosis. In the HepG2 cell line, released Fe³⁺ and Cu²⁺ react with GSH to form Fe²⁺ and Cu⁺, thereby damaging the antioxidant system. To promote ferroptosis, these ions react with H₂O₂ in Fenton/Fenton-like ways, producing harmful hydroxyl radicals (•OH). High-valent Fe³⁺ and Cu²⁺ are created in the meantime, creating a cycle that depletes GSH and generates •OH. When H₂O₂ is depleted, the cells’ increased Cu⁺ level leads to the aggregation of lipoylated proteins, which intensifies cuproptosis. 5CFGH showed excellent cell-killing efficiency against HCC. Overall, 5CFGH is a possible drug that could induce self-amplification of cuproptosis/ferroptosis in HCC.</p> Graphical Abstract <p></p>