5-HT Reuptake Blockade Disrupts Genomic Stability-Based proteostasis to Induce Pyroptosis via Remodeling Histone Serotonylation [RNA-seq]

The dual challenges of limited therapeutic options caused by de novo or acquired resistance and psychological distress in melanoma patients necessitate innovative treatment strategies. In this study, we identify Paroxetine Hydrochloride (PH), an FDA-approved antidepressant, as a novel therapeutic agent for BRAFV600E-mutated melanoma, including BRAFi/MEKi-resistant cases. Furthermore, our findings unraveled that PH acts as an unrecognized pyroptosis inducer. By triggering pyroptosis, PH remodels the tumor microenvironment to synergize with anti-PD-1 therapy while maintaining a favorable safety profile. Mechanistically, PH impedes serotonin reuptake, leading to epigenetic reprogramming through reduced histone serotonylation at the promoters of DNA repair genes. The impairment of DNA damage repair pathways in turn triggers genomic instability, proteostasis imbalance, and 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 melanoma treatment.