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Updated: Feb 4, 2026

siRNA Screening to Identify Ubiquitin and Ubiquitin-like System Regulators of Biological Pathways in Cultured Mammalian Cells
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A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis

Li Wang1, Hao Cai2, Youtian Hu1

  • 1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.

Cell Death & Disease
|September 28, 2018
PubMed

Insights

A novel inhibitor, CH004, targets cystathionine β-synthase (CBS) to suppress liver cancer growth. Inhibiting CBS disrupts the transsulfuration pathway, leading to ferroptosis and reduced tumor progression.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Cystathionine β-synthase (CBS) catalyzes the initial step in sulfur amino acid transsulfuration.
  • The roles of CBS and the transsulfuration pathway in cell proliferation and death are not fully understood.

Purpose of the Study:

  • To investigate the function and mechanism of CBS in cell proliferation and death.
  • To develop and characterize a novel CBS inhibitor for potential therapeutic applications in liver cancer.

Main Methods:

  • Design, synthesis, and in vitro/in vivo validation of a bioactive CBS inhibitor (CH004).
  • Assay of CBS activity, homocysteine levels, and hydrogen sulfide production.
  • Inhibition of CBS via chemical or genetic means.
  • Evaluation of CH004 efficacy in a liver cancer xenograft mouse model.

Main Results:

  • CH004 effectively inhibits human CBS activity in vitro and in vivo.
  • CH004 treatment led to increased cellular homocysteine and decreased hydrogen sulfide production in a dose-dependent manner.
  • CBS inhibition was found to be coupled with cell proliferation and cell cycle regulation.
  • CH004 significantly suppressed tumor growth in a liver cancer xenograft model.
  • Inhibition of CBS induced ferroptosis in hepatocellular carcinoma cells.

Conclusions:

  • Endogenous CBS plays a critical role in liver cancer cell proliferation.
  • Inhibition of CBS by CH004 represents a potential therapeutic strategy for liver cancer by inducing ferroptosis.
  • The study highlights the intricate connections between the transsulfuration pathway, ferroptosis, and liver cancer.

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