Abstract

The dual challenges of limited therapeutic options due to de novo or acquired resistance and psychological distress in patients with melanoma necessitate innovative treatment strategies. Here, we identify paroxetine hydrochloride (PH), a Food and Drug Administration (FDA)-approved antidepressant, as an alternative therapeutic for BRAF V600E -mutated melanoma, including BRAFi/MEKi-resistant cases. Furthermore, our findings reveal that PH acts as an unrecognized inducer of pyroptosis. By triggering pyroptosis, PH remodels the tumor-permissive microenvironment in recurrent melanoma to potentiate anti-PD-1 therapy while maintaining a favorable safety profile. Mechanistically, PH impedes 5-hydroxytryptamine (5-HT) reuptake, leading to epigenetic reprogramming by reducing histone serotonylation (H3Q5ser) at the promoters of DNA repair genes. Impaired DNA damage repair pathways in turn trigger genome instability, proteostasis imbalance, and subsequent endoplasmic reticulum stress, ultimately inducing pyroptosis. Our findings uncover the underlying mechanism by which 5-HT drives melanoma progression and highlight PH as a promising candidate with multiple clinical potentials for treating melanoma.