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

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.

ORGANISM(S): Mus musculus

PROVIDER: GSE276373 | GEO | 2024/11/24

REPOSITORIES: GEO

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

Project description: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.

2024-11-24 | GSE276370 | GEO

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

Project description:Melanoma bone metastasis-induced osteocyte ferroptosis via the HIF1α-HMOX1 axis.

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

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Autophagy of OTUD5 Destabilizes GPX4 to Confer Ferroptosis-Dependent Kidney Injury

Project description:Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We show that OTU deubiquitinase 5 (OTUD5) is a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. In this work, our study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

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Project description:Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by the generation of excess reactive oxygen species (ROS) and lipid peroxidation. However, it remains largely unknown whether signaling pathways, such as the ROS-activated mitogen-activated protein kinase (MAPK) pathways, affect ferroptosis. The c-Jun N-terminal kinase (JNK), a MAPK signaling molecule that plays an essential role in apoptosis, is activated in response to various stimuli, including oxidative stress. In this study, we examined the functional role of JNK in cell death induced by imidazole ketone erastin (IKE), a potent ferroptosis inducer, using gene knockout technology. We found that JNK1/2 double-knockout cells, but not JNK1 or JNK2 single-knockout cells, were much more tolerant to IKE-induced cell death compared to control cells. We further demonstrated that IKE-induced increase in CTH and HMOX1, key genes in ferroptosis, in control cells was substantially suppressed by the depletion of JNK1 and JNK2. These results suggested that JNK1 and JNK2 play an important, overlapping role in ferroptosis. Our findings advance our understanding of the JNK pathway, which could contribute to future pharmacological developments in ferroptosis-related diseases such as cancer and neurodegeneration.

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