Capitalising on the tripartite pharmacological profile of SSPH I, this study aims to elucidate the regulatory mechanisms of Erk1/2 in ferroptosis and oxidative stress pathways and analyse their feedback regulatory effects on Erk1/2 while systematically investigating the anti‐hepatocellular carcinoma efficacy and underlying mechanisms of SSPH I through integrated in vitro and in vivo approaches. This evidence concerns the gene MAPK3 and hepatocellular carcinoma.