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

ABSTRACT: Evasion of programmed cell death (PCD) is a hallmark of cancer, yet the mechanisms underlying resistance to ferroptosis - an iron-dependent form of PCD triggered by excessive lipid peroxidation - remain incompletely understood. Here, we identify a previously unrecognized nucleolar-mitochondrial signaling axis that promotes ferroptosis resistance in pleural mesothelioma (PM) and potentially other cancers. This pathway involves RNA polymerase I (PolI) catalytic subunit A (POLR1A) and mitochondrial transcription factor A (TFAM), which together regulate mitophagy and intracellular iron metabolism to suppress ferroptosis. Mechanistically, POLR1A controls TFAM expression via the transcription factor ATF4, and this POLR1A-ATF4-TFAM axis inhibits mitophagy and limit mitophagy-dependent labile Fe

SUBMITTER: Zhang T 

PROVIDER: S-EPMC12281011 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature