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

Our plain-English summary of POLR1A inhibits ferroptosis by regulating TFAM-mediated mitophagy and iron homeostasis, by T. Zhang, Y. Gao, M. Harhai, et al (Redox Biology, 2025).

The study

• Authors: T. Zhang, Y. Gao, M. Harhai, A.A. Jourdain, T.M. Marti, E. Vassella, Z. Yang, Q. Zhou, P. Dorn, R.W. Peng
• Journal: Redox Biology
• Published: 2025;85:103758
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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 Fe2+ release, thereby preventing Fe2+-driven lipid peroxidation. Disruption of this pathway through POLR1A or TFAM inhibition leads to Fe2+ accumulation and increased sensitivity to ferroptosis inducers (FINs). Notably, CX-5461, a first-in-class RNA PolI inhibitor currently in clinical trials, synergizes with GPX4 blockade to induce ferroptotic cell death both in vitro and in vivo. This therapeutic synergy extends beyond PM, suggesting broader relevance in ferroptosis-resistant cancers. Together, our findings reveal a novel mechanism of ferroptosis evasion and establish a promising combinatorial strategy to overcome therapy resistance in cancer.

Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.

In plain English

This laboratory study of pleural mesothelioma (PM) examined whether the RNA polymerase I catalytic subunit POLR1A protects cancer cells from ferroptosis. Using DepMap CRISPR screening data across 16 PM cell lines, the authors found ribosome biogenesis to be the pathway most associated with PM cell dependency and POLR1A to have the highest average dependency score among polymerase I subunits; higher POLR1A mRNA was associated with worse overall survival in the TCGA-MESO cohort (n = 87). In MESO1 and H2452 cells, knockdown of POLR1A lowered ATF4 and TFAM levels, reduced mitochondrial membrane potential and oxygen consumption, and increased mitophagy and labile Fe2+; TFAM overexpression restored membrane potential, mitophagy and Fe2+, while PARK2 silencing reduced the raised mitophagy and Fe2+. POLR1A- or TFAM-depleted cells showed more cell death and lipid peroxidation with the GPX4 inhibitor RSL3; ferrostatin-1 or TFAM overexpression rescued these effects, and the rise in lipid peroxidation was also abolished by deferoxamine. In MESO1 xenografts in NSG mice, CX-5461 combined with GPX4 knockout inhibited tumour growth, an effect reversed by liproxstatin-1. The authors concluded that the POLR1A-ATF4-TFAM axis restrains mitophagy-driven iron release and ferroptosis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study in cancer cell lines and mouse xenografts, combined with bioinformatic analysis of public genomic, dependency and single-cell datasets
• Who was studied: Human pleural mesothelioma and other cancer cell lines (MESO-1, H2452, BE1143T, H1080T, DLD1); 16 PM cell lines in DepMap; TCGA-MESO patients (n = 87); single-cell RNA-seq from 3 treatment-naive PM samples; 8-week-old male NSG mice
• Exposure: Genetic knockdown/knockout of POLR1A, TFAM, ATF4, PARK2 and GPX4, and drug treatment with RNA PolI inhibitors (CX-5461, quarfloxin, BMH-21, actinomycin D) and ferroptosis inducers (RSL3, ML162, erastin), with ferrostatin-1, liproxstatin-1 or deferoxamine as rescues
• Main results:
  • In DepMap CRISPR data across 16 PM cell lines, ribosome biogenesis was the pathway most associated with PM cell dependency
  • Among the RNA polymerase I subunits, POLR1A had the highest average dependency score
  • Higher POLR1A mRNA correlated with worse overall survival in the TCGA-MESO cohort of 87 patients
  • POLR1A knockdown in PM cells lowered TFAM mRNA and protein
  • POLR1A knockdown also reduced ATF4 protein, and ATF4 knockdown lowered while ATF4 overexpression raised TFAM
  • Knockdown of POLR1A or TFAM increased mitophagy in PM cells, and this was reversed by TFAM overexpression
  • Knockdown of POLR1A or TFAM increased labile Fe2+ in MESO1 and H2452 cells; TFAM overexpression restored baseline Fe2+
  • PARK2 silencing rescued the elevated mitophagy and Fe2+ accumulation caused by POLR1A or TFAM knockdown
  • POLR1A- or TFAM-depleted cells showed higher lipid peroxidation with RSL3; the increase was abolished by ferrostatin-1, deferoxamine or TFAM overexpression
  • Ferrostatin-1 or TFAM overexpression rescued the greater loss of viability, impaired colony formation and increased cell death seen in POLR1A KD and TFAM KD cells treated with RSL3
  • POLR1A knockdown raised SLC7A11 but did not sensitise MESO1 and H2452 cells to erastin
  • In MESO1 xenografts in NSG mice, CX-5461 with GPX4 knockout inhibited tumour growth, reversed by liproxstatin-1
  • Combination of CX-5461 and RSL3 also reduced viability in primary PM cells (BE1143T), sarcoma (H1080) and colon cancer (DLD1) lines
• The authors' conclusion: The authors concluded that they identified a POLR1A-TFAM signalling axis linking nucleolar function to mitophagy, iron regulation and ferroptosis resistance, providing a rationale for combining PolI inhibition with ferroptosis inducers
• Limitations the authors state:
  • The authors state that whether POLR1A confers ferroptosis resistance through an SLC7A11-independent mechanism is unresolved
  • In the mouse experiments, sample size was not determined statistically and allocation was not blinded
  • The authors note the focus was on pleural mesothelioma, with relevance to other cancers only suggested

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Clinical Trial.

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