2. Academic Validation
  3. Melanoma bone metastasis-induced osteocyte ferroptosis via the HIF1α-HMOX1 axis

Melanoma bone metastasis-induced osteocyte ferroptosis via the HIF1α-HMOX1 axis

  • Bone Res. 2025 Jan 16;13(1):9. doi: 10.1038/s41413-024-00384-y.
Yewei Jia 1 2,  Rui Li 3,  Yixuan Li 1 2,  Katerina Kachler 1 2,  Xianyi Meng 1 2,  Andreas Gießl 4,  Yi Qin 1 2,  Fulin Zhang 1 2,  Ning Liu 1 2,  Darja Andreev 1 2 5,  Georg Schett 1 2,  Aline Bozec 6 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 2 Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 3 Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of Opthalmology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 5 Technische Universität Dresden (TUD), Center for Molecular and Cellular Bioengineering (CMCB), Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany.
  • 6 Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany. aline.bozec@uk-erlangen.de.
  • 7 Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany. aline.bozec@uk-erlangen.de.
PMID: 39814705 DOI: 10.1038/s41413-024-00384-y
Abstract

Osteocytes are the main cells in mineralized bone tissue. Elevated osteocyte Apoptosis has been observed in lytic bone lesions of patients with multiple myeloma. However, their precise contribution to bone metastasis remains unclear. Here, we investigated the pathogenic mechanisms driving melanoma-induced osteocyte death. Both in vivo models and in vitro assays were combined with untargeted RNA Sequencing approaches to explore the pathways governing melanoma-induced osteocyte death. We could show that Ferroptosis is the primary mechanism behind osteocyte death in the context of melanoma bone metastasis. HMOX1 was identified as a crucial regulatory factor in this process, directly involved in inducing Ferroptosis and affecting osteocyte viability. We uncover a non-canonical pathway that involves excessive autophagy-mediated ferritin degradation, highlighting the complex relationship between Autophagy and Ferroptosis in melanoma-induced osteocyte death. In addition, HIF1α pathway was shown as an upstream regulator, providing a potential target for modulating HMOX1 expression and influencing autophagy-dependent Ferroptosis. In conclusion, our study provides insight into the pathogenic mechanisms of osteocyte death induced by melanoma bone metastasis, with a specific focus on Ferroptosis and its regulation. This would enhance our comprehension of melanoma-induced osteocyte death.

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