Integrative Gut Microbiota and Metabolomic Analyses Reveal the PANoptosis- and Ferroptosis-Related Mechanisms of Chrysoeriol in Inhibiting Melanoma

Chrysoeriol, a natural flavonoid, has shown potential in inhibiting melanoma. However, the detailed molecular mechanisms of its action still need to be clarified. In this study, chrysoeriol showed significant suppressive effects on melanoma progression in a mouse model. The integrative gut microbiota and metabolomic analyses revealed that chrysoeriol modulates multiple pathways associated with apoptosis, necroptosis, pyroptosis, and ferroptosis. Morphological changes in chrysoeriol-treated melanoma cells showed PANoptosis- and ferroptosis-related characteristics. Additionally, chrysoeriol induced apoptosis, altered mitochondrial membrane potential, increased ROS production, promoted necroptosis, and also upregulated molecules linked to pyroptosis and ferroptosis. Molecular-level experiments confirmed that chrysoeriol promoted the upregulation of crucial proteins associated with the PANoptosis and ferroptosis pathways. Inhibition of PANoptosis and ferroptosis pathways by inhibitors or gene knockdown significantly attenuated the inhibitory effects of chrysoeriol on melanoma cell viability. This study provides robust evidence that chrysoeriol triggers both PANoptosis and ferroptosis in melanoma cells, underscoring its promise as a treatment option for melanoma.