• Sanguinarine (San) inhibits HCC cell proliferation, migration, and EMT while promoting apoptosis in vitro and suppresses tumor growth in vivo.
• San induces cuproptosis by increasing copper levels, upregulating FDX1, LIAS, HSP70, and lipoylated DLAT aggregation, and reducing mitochondrial membrane potential and glutathione/pyruvate levels.
• San directly binds to FDX1, enhancing its thermostability, and FDX1 silencing attenuates San's anti-HCC effects, confirming FDX1 as a key target.
• Combining San with copper ionophores synergistically enhances cuproptosis, suggesting a potential therapeutic strategy for HCC.