Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS-mitochondrial...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Non-small-cell lung cancer (NSCLC) treatment outcomes are limited by resistance and toxicity.
• Erastin (ferroptosis inducer) and celastrol (anticancer triterpene) show potential but have limitations.
• Combination therapy offers a strategy to enhance efficacy and reduce side effects.

Purpose of the Study:

• To investigate the synergistic effects of erastin and celastrol in NSCLC treatment.
• To elucidate the underlying molecular mechanisms of the combined therapy.
• To evaluate the therapeutic potential of this combination for NSCLC.

Main Methods:

• Assessed cell death induction by erastin and celastrol alone and in combination.
• Measured reactive oxygen species (ROS) generation and mitochondrial membrane potential.
• Investigated autophagy, mitophagy (ATG5/ATG7, PINK1/Parkin), heat shock protein (HSP) expression (HSF1), and performed HSF1 knockdown in vitro and in vivo.

Main Results:

• Erastin and celastrol synergistically induced NSCLC cell death at non-toxic concentrations.
• Combined treatment increased ROS, disrupted mitochondrial membrane potential, and promoted mitochondrial fission.
• Cotreatment initiated autophagy, mitophagy, and HSP expression in an HSF1-dependent manner; HSF1 knockdown enhanced cell death and inhibited tumor growth.

Conclusions:

• The combination of erastin and celastrol demonstrates significant synergistic anticancer effects in NSCLC.
• The mechanism involves ROS generation, mitochondrial dysfunction, autophagy, mitophagy, and HSF1-mediated HSP expression.
• This combination represents a promising novel therapeutic strategy for NSCLC requiring further clinical investigation.