POLR1A inhibits ferroptosis by regulating TFAM-mediated mitophagy and iron homeostasis

Area of Science:

• Cell Biology
• Cancer Biology
• Biochemistry

Background:

• Evasion of programmed cell death (PCD) is a critical hallmark of cancer.
• Mechanisms of resistance to ferroptosis, an iron-dependent PCD, are not fully understood.
• Lipid peroxidation and iron metabolism are key regulators of ferroptosis.

Purpose of the Study:

• To identify novel mechanisms of ferroptosis resistance in cancer.
• To elucidate the role of a nucleolar-mitochondrial signaling axis in ferroptosis evasion.
• To explore therapeutic strategies targeting ferroptosis resistance.

Main Methods:

• Investigated the role of RNA polymerase I (POLR1A) and mitochondrial transcription factor A (TFAM) in ferroptosis.
• Utilized RNA interference and pharmacological inhibitors to disrupt the POLR1A-ATF4-TFAM axis.
• Assessed ferroptosis induction and cell death in cancer models in vitro and in vivo.
• Examined the synergistic effects of RNA PolI inhibition and GPX4 blockade.

Main Results:

• Identified a POLR1A-ATF4-TFAM signaling axis that suppresses ferroptosis by inhibiting mitophagy and limiting labile iron (Fe2+) release.
• Disruption of this pathway leads to Fe2+ accumulation and increased sensitivity to ferroptosis inducers.
• CX-5461, an RNA PolI inhibitor, synergizes with GPX4 blockade to induce ferroptotic cell death.
• This pathway is relevant in pleural mesothelioma and potentially other ferroptosis-resistant cancers.

Conclusions:

• A novel nucleolar-mitochondrial pathway involving POLR1A and TFAM confers resistance to ferroptosis.
• Targeting this pathway offers a promising strategy to overcome cancer therapy resistance.
• Combinatorial therapy with RNA PolI inhibitors and ferroptosis inducers shows therapeutic potential.