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Updated: May 15, 2026

Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
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H2S induces apoptosis of tumors with high IDO1 expression via NR4A1-BCL-2 and SOCS3 pathways

Zhen Ning Tony He1, Fangzhou Meng1, Xiaoyang Qian1

  • 1State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Songhu Road 2005, Shanghai, 200438, China.

Cellular & Molecular Biology Letters
|May 14, 2026
PubMed
Abstract

Insights

Hydrogen sulfide (H2S) demonstrates antitumor effects by inducing apoptosis in tumor cells with high indoleamine 2,3-dioxygenase 1 (IDO1) expression. This occurs through the NR4A1-BCL-2 pathway and IDO1/SOCS3 codegradation, offering a novel cancer therapy strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Hydrogen sulfide (H2S) exhibits dual roles in cancer, acting as both a protumor and antitumor agent.
  • Clarifying the conditions and mechanisms underlying H2S's antitumor effects is crucial for therapeutic development.
  • Previous research linked H2S to the immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), suggesting H2S downregulates IDO1.

Purpose of the Study:

  • To investigate the antitumor effects of H2S in relation to IDO1 expression in tumor cells.
  • To elucidate the molecular mechanisms by which H2S induces apoptosis in IDO1-expressing tumors.
  • To evaluate the therapeutic potential of H2S against IDO1-high tumors in vivo.

Main Methods:

  • Assessing apoptosis and cellular distribution of NR4A1.
  • Examining IDO1 phosphorylation and its binding with SOCS3.
  • In vitro and in vivo experiments in tumor cell lines and tumor-bearing mice.

Main Results:

  • H2S significantly reduces proliferation and induces apoptosis in tumor cells with high IDO1 expression.
  • H2S promotes NR4A1 nuclear export and binding with BCL-2, alongside IDO1 phosphorylation.
  • Tumor-bearing mice treated with H2S exhibited significant therapeutic effects against IDO1-high tumors.

Conclusions:

  • H2S induces tumor cell apoptosis via the NR4A1-BCL-2 pathway and promotes the codegradation of phosphorylated IDO1 and SOCS3.
  • This study provides novel theoretical and experimental evidence supporting H2S as a potential cancer therapeutic agent.
  • The findings highlight the importance of IDO1 expression levels in determining H2S's efficacy.
Keywords:
ApoptosisHydrogen sulfideIndoleamine 2,3-dioxygenase 1Tumor therapy

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