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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282621 | GEO | 2025/11/20

REPOSITORIES: GEO

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Project description:Serotonin (5-hydroxytryptamine) plays a critical role in human development in utero. Recent evidence suggests that it is taken up from the maternal circulation and gets concentrated in trophoblasts (Kliman et al., 2018). A novel mechanism involving serotonin has been described: serotonylation, a covalent linkage of 5-HT with protein glutamines mediated by a tissue transglutaminase (Farelly et al., 2019). Our objective was to understand the role of serotonin, through serotonylation, in protein, gene and phenotype expression in human placenta. Trophoblast puriScation and culture, western blot (WB), immunochemistry (IHC), and RNAseq (with IPA) were performed. Experiments were repeated at least 3 times, and corresponding statistical analysis was done. Through WB and IHC, we found that serotonylation seems to be present in human placenta and cytotrophoblasts. Moreover, through IHC and RNAseq/IPA, serotonylation seems to have consequences on gene and phenotype expression; especially on fusion, proliferation and invasion, which leads to implantation and placental structure, initial steps of pregnancy. Through IPA analysis, those phenotype and serotonylation impacted-genes were also found to be involved in embryonic, organismal, tissue and organ development, and especially the brain and behavior, foreshadowing central role in human body physiological development. Lastly, IPA results also showed that those same genes were also involved in many different pathologies, especially ones like Alzheimer, Parkinson, ALS, depression, ASD or cancer (EMT). To conclude, these Sndings seem to show that the human placenta, through the cytotrophoblast, is an essential organ to understand the origin of human life and pathophysiological development. Serotonin, through serotonylation, seems to be central by regulating original embryonic genes involved in different processes during life, especially in initiation of pregnancy (invasion and placentation), development of the human body, behavior, and different pathologies, leading to potential diagnostic or therapeutic options for patients.

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

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