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TrxR Inhibition and Nrf2-FOXO3 Modulation by Repurposed Drugs: A Redox Strategy to Reverse Cancer Multidrug

Charan Singh Pawar1, Nagarajan Rajendra Prasad1

  • 1Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, Tamil Nadu, India.

Drug Development Research
|July 30, 2026
PubMed

Insights

Redox-based drug repurposing combats multidrug-resistant (MDR) cancer by re-sensitizing tumors to chemotherapy. Targeting imbalanced redox signaling with repurposed drugs like metformin and auranofin shows promise for improved cancer treatment outcomes.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Multidrug-resistant (MDR) cancer is often driven by imbalanced redox signaling, which impairs chemotherapy efficacy and promotes cancer cell survival.
  • Key mechanisms in MDR include thioredoxin reductase (TrxR) amplification and Keap1-Nrf2-FOXO3 pathway activation, leading to increased drug efflux and antioxidant defenses.

Purpose of the Study:

  • To explore redox-based drug repurposing as a strategy to overcome MDR in cancer.
  • To investigate the potential of repurposed drugs to restore chemosensitivity by targeting redox signaling pathways.

Main Methods:

  • Review of preclinical studies on repurposed drugs (metformin, auranofin, brusatol, natural polyphenols) that modulate redox signaling.
  • Examination of nanotechnology advancements, combination therapies (with anticancer drugs, ferroptosis inducers), and redox-responsive delivery systems.
  • Focus on biomarker-driven patient classification based on TrxR expression or Keap1/Nrf2 mutations.

Main Results:

  • Repurposed drugs increase reactive oxygen species (ROS), enhancing MDR cell sensitivity to chemotherapy by inhibiting Nrf2 or TrxR.
  • Nanotechnology and combination therapies improve tumor selectivity and reduce systemic toxicity.
  • Preclinical data demonstrate suppression of antioxidant pathways, inhibition of efflux pumps, and effective redox-responsive drug delivery.

Conclusions:

  • Redox-targeted drug repurposing is a viable precision strategy for overcoming MDR cancer and restoring chemosensitivity.
  • Future directions include advanced delivery systems, adaptive clinical trials, and specific redox profiling for clinical translation.
Keywords:
Keap1–Nrf2–FOXO3 signaling pathwayROSauranofinmultidrug resistancerepurposed drugsthioredoxin reductase

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