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Unmasking the apoptotic potential of DHODH inhibition through targeting adaptive mitophagy

Xiaowen Huang1,2, Zichang Guo2, Bowen Liu2,3

  • 1School of Life Sciences, Fudan University, Shanghai, China.

Frontiers in Cell and Developmental Biology
|June 1, 2026
PubMed

Insights

Dihydroorotate dehydrogenase (DHODH) inhibitors show promise in cancer therapy. Combining DHODH inhibitors with mitophagy inhibitors enhances anti-tumor activity by increasing mitochondrial damage and apoptosis.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Drug Discovery

Background:

  • Targeting de novo pyrimidine synthesis via dihydroorotate dehydrogenase (DHODH) is a key anticancer strategy.
  • DHODH inhibitors like brequinar (BQR) have limited single-agent efficacy due to adaptive resistance mechanisms.

Purpose of the Study:

  • To investigate the adaptive mechanisms limiting DHODH inhibitor efficacy.
  • To explore combination therapies to overcome resistance to DHODH inhibitors.

Main Methods:

  • Utilized mt-Keima-based mitophagy reporters to monitor mitophagy.
  • Employed CRISPR/Cas9 gene knockout models to study resistance mechanisms.
  • Assessed synergistic effects of combining DHODH and mitophagy inhibitors in vitro and in vivo.

Main Results:

  • Brequinar (BQR) treatment induces mitochondrial reactive oxygen species (mtROS), triggering protective mitophagy.
  • Inhibiting mitophagy synergistically enhances BQR's anti-tumor activity.
  • The combination therapy leads to increased mtROS, lipid peroxidation, and caspase-dependent apoptosis.

Conclusions:

  • Mitophagy acts as a crucial adaptive resistance mechanism against DHODH inhibitors.
  • Combining DHODH inhibitors with mitophagy inhibitors represents a promising strategy to enhance anti-cancer efficacy.
  • This approach warrants further investigation for clinical translation in cancer treatment.
Keywords:
ATG7DHODH inhibitionapoptosischloroquinemitophagymtROS

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