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Updated: Jan 13, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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5-HT reuptake blockade induces pyroptosis in BRAFV600E-mutated melanomas via remodeling histone serotonylation

Aicun Li1, Shoujia Xu2, Jiachen Fan1

  • 1The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning, China.

Cell Reports. Medicine
|January 6, 2026
PubMed

Insights

Paroxetine hydrochloride, an antidepressant, shows promise for treating BRAF V600E melanoma, even resistant forms. It induces pyroptosis, enhancing anti-PD-1 therapy by reprogramming the tumor microenvironment.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Melanoma presents challenges with drug resistance and psychological distress, requiring novel therapeutic approaches.
  • Existing treatments for BRAF V600E melanoma face limitations due to acquired resistance.
  • The tumor microenvironment significantly influences treatment efficacy and patient outcomes.

Purpose of the Study:

  • To identify novel therapeutic agents for BRAF V600E melanoma, including resistant subtypes.
  • To investigate the potential of paroxetine hydrochloride (PH) as an anti-melanoma agent.
  • To elucidate the mechanism of action of PH in melanoma, focusing on pyroptosis induction and its impact on the tumor microenvironment.

Main Methods:

  • In vitro and in vivo models of BRAF V600E melanoma, including drug-resistant cell lines.
  • Assessment of paroxetine hydrochloride's efficacy, safety profile, and mechanism of action.
  • Analysis of pyroptosis induction, epigenetic modifications (histone serotonylation), DNA damage repair pathways, and tumor microenvironment remodeling.
  • Evaluation of combination therapy with anti-PD-1 agents.

Main Results:

  • Paroxetine hydrochloride (PH) demonstrates therapeutic potential against BRAF V600E melanoma, including BRAFi/MEKi-resistant cases.
  • PH induces pyroptosis, a programmed cell death pathway, in melanoma cells.
  • PH remodels the tumor microenvironment, enhancing the efficacy of anti-PD-1 therapy.
  • Mechanistically, PH inhibits 5-hydroxytryptamine (5-HT) reuptake, leading to reduced histone serotonylation (H3Q5ser) at DNA repair gene promoters, causing DNA damage and subsequent pyroptosis.
  • PH exhibits a favorable safety profile.

Conclusions:

  • Paroxetine hydrochloride is identified as a potential repurposed drug for melanoma treatment.
  • PH's ability to induce pyroptosis and remodel the tumor microenvironment offers a novel strategy to overcome resistance and potentiate immunotherapy.
  • Understanding the role of 5-HT signaling in melanoma progression opens new therapeutic avenues targeting epigenetic reprogramming and DNA repair pathways.
Keywords:
5-hydroxytryptamineBRAF mutationdrug repurposingdrug resistancegenomic instabilityhistone serotonylationimmunotherapymelanomaproteostasispyroptosis

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