<p>Ferroptosis has been closely linked to the pathological processes of various diseases, making it a promising target for therapeutic intervention. Understanding the regulatory mechanisms underlying ferroptosis and developing effective pharmacological strategies is essential. Nanomedicine, particularly the use of nanozymes, offers a potential approach for regulating ferroptosis. In this study, we investigated the inhibitory activity of ultra-small, biocompatible cerium oxide nanoparticles (CeO₂ NPs) on ferroptosis and explored the underlying molecular mechanisms. CeO₂ NPs exhibited potent superoxide dismutase (SOD) and catalase (CAT) activities, efficiently scavenging multiple free radicals and lipid peroxidation products both intracellularly and extracellularly. These activities effectively prevented or alleviated ferroptosis in RSL3-induced cells. Proteomic analysis revealed that CeO₂ NPs significantly altered the expression of numerous proteins, including a reduction in pro-inflammatory cytokines. Mechanistically, CeO₂ NPs specifically regulated the expression of key proteins involved in ferroptosis-related metabolic processes, reducing iron accumulation and lipid peroxidation, and thereby decreasing cellular susceptibility to ferroptosis. Our findings demonstrate that CeO₂ NPs synergistically inhibit ferroptosis by both scavenging reactive oxygen species (ROS) and modulating the expression of ferroptosis-regulating proteins. In conclusion, this study highlights the potential of CeO₂ NPs as a promising nanozymes for ferroptosis inhibition, offering novel insights into the design of CeO₂ NPs-based therapies for ferroptosis-related diseases.</p> Graphical Abstract <p></p>