HMOX1 controls a heme-ferritin switch that protects cells from ferroptosis
Modulating the intracellular labile iron pool (LIP) has emerged as a promising strategy to induce ferroptosis in cancer cells, offering a way to overcome resistance to apoptosis-based therapies. One of the main contributors to LIP is heme catabolism mediated by heme oxygenase-1 (HMOX1), which promotes ferroptosis sensitivity by releasing free iron. Beyond its role as an iron donor, heme can influence diverse proteins and signaling pathways that drive tumor progression, but how heme regulates ferroptosis remains poorly understood. Here, we uncover a paradoxical, protective function of heme in the absence of HMOX1 activity. When HMOX1 is inactive, heme becomes stabilized, leading to ferritin up-regulation, suppression of ferroptosis, and rescue of cell death induced by both pharmacological and genetic inhibition of GPX4. Our findings reveal an unrecognized heme-HMOX1-ferritin axis that controls ferroptosis sensitivity. Targeting this pathway may offer a new therapeutic strategy to modulate ferroptosis in cancer.
Authors
- Clarissa Ribeiro Reily Rocha (ORCID: https://orcid.org/0000-0001-9634-4307)
- Ana Beatriz da Silva Teixeira (ORCID: https://orcid.org/0000-0003-2659-6714)
- Ancély Ferreira dos Santos (ORCID: https://orcid.org/0000-0003-4985-6187)
- Gholamreza Fazeli (ORCID: https://orcid.org/0000-0002-1367-1941)
- José Pedro Friedmann Angeli (ORCID: https://orcid.org/0000-0001-7706-1379)
- Werner Schmitz (ORCID: https://orcid.org/0000-0003-0485-7303)
- Florêncio Porto Freitas (ORCID: https://orcid.org/0000-0002-0369-4488)
- Maria Carolina Clares Ramalho (ORCID: https://orcid.org/0000-0001-7122-6152)
- Izadora de Souza (ORCID: https://orcid.org/0000-0002-6935-7521)
- Karoline Almeida (ORCID: https://orcid.org/0000-0003-0889-155X)
- Izabela Amélia Marques de Andrade
Institutions
- University of Würzburg (DE)
- Centre Virchow-Villermé (FR)
- Universidade Federal de São Paulo (BR)
Publication Details
- Journal
- Science Advances
- Published
- 2026-08-19
- DOI
- https://doi.org/10.1126/sciadv.aeg3424
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- José Carreras Leukämie-Stiftung
- Julius-Maximilians-Universität Würzburg
- Horizon 2020 Framework Programme
- European Research Council