N6-methyadenosine-modified YWHAE mRNA promotes proliferation and inhibits ferroptosis in hepatoblastoma by mediating SLC7A11 expression
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Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Advances in ferroptosis for castration-resistant prostate cancer treatment: novel drug targets and combination therapy strategies
Metastatic prostate cancer (PCa) has much lower survival and ultimately develops castration resistance, which expects novel targets and therapeutic approaches. As a result of iron-dependent lipid peroxidation, ferroptosis triggers programmed cell death and has been associated with castration-resistant prostate cancer (CRPC).
Decreased miR-128-3p in serum exosomes from polycystic ovary syndrome induces ferroptosis in granulosa cells via the p38/JNK/SLC7A11 axis through targeting CSF1
Increasing evidence suggests that non-coding small RNAs (miRNAs) carried by exosomes (EXOs) play important roles in the development and treatment of polycystic ovary syndrome (PCOS). In this study, we demonstrate that PCOS mouse serum-derived EXOs promote granulosa cells (GCs) ferroptosis, and induce the occurrence of a PCOS-like phenotype in vivo. Notably, EXO miRNA sequencing combined with in vitro gain- and loss-of-function assays revealed that miR-128-3p, which is absent in the serum-derived EXOs of mice with PCOS, regulates lipid peroxidation and GC sensitivity to ferroptosis inducers. Mechanistically, overexpression of CSF1, a direct target of miR-128-3p, reversed the anti-ferroptotic effect of miR-128-3p. Conversely, ferroptosis induction was mitigated in CSF1-downregulated GCs. Furthermore, we demonstrated that miR-128-3p inhibition activates the p38/JNK pathway via CSF1, leading to NRF2-mediated down-regulation of SLC7A11 transcription, which triggers GC iron overload. Moreover, intrathecal miR-128-3p AgomiR injection into mouse ovaries ameliorated PCOS-like characteristics and restored fertility in letrozole-induced mice. The study reveals the pathological mechanisms of PCOS based on circulating EXOs and provides the first evidence of the roles of miR-128-3p and CSF1 in ovarian GCs. This discovery is expected to provide promising therapeutic targets for the treatment of PCOS.
Insights on the crosstalk among different cell death mechanisms
The phenomenon of cell death has garnered significant scientific attention in recent years, emerging as a pivotal area of research. Recently, novel modalities of cellular death and the intricate interplay between them have been unveiled, offering insights into the pathogenesis of various diseases. This comprehensive review delves into the intricate molecular mechanisms, inducers, and inhibitors of the underlying prevalent forms of cell death, including apoptosis, autophagy, ferroptosis, necroptosis, mitophagy, and pyroptosis. Moreover, it elucidates the crosstalk and interconnection among the key pathways or molecular entities associated with these pathways, thereby paving the way for the identification of novel therapeutic targets, disease management strategies, and drug repurposing.
Melanoma bone metastasis-induced osteocyte ferroptosis via the HIF1α-HMOX1 axis
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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