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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.
Cholesterol homeostasis and lipid raft dynamics at the basis of tumor-induced immune dysfunction in chronic lymphocytic leukemia
Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.
Melatonin affects trophoblast epithelial-to-mesenchymal transition and oxidative damage resistance by modulating GDF15 expression to promote embryo implantation
Melatonin is widely observed in the female reproductive system and regulates trophoblast cell functions, but its effects on embryo implantation and underlying mechanisms are not well understood. By constructing an in vitro embryo culture model, we found that melatonin enhances migration and implantation in human and mouse trophoblast cells. It also significantly promoted HTR-8/SVneo cell proliferation, inhibited apoptosis, enhanced migration, and mitigated oxidative damage. Further investigation revealed that melatonin promoted trophoblast cell migration and increased the in vitro implantation rate of HTR-8/SVneo spheroids by promotes epithelial-mesenchymal transition (EMT) via the growth differentiation factor 15 (GDF15)–mothers against decapentaplegic homolog 2/3 (SMAD2/3) pathway. Additionally, melatonin increased the levels of glutathione peroxidase 4 (GPX4) and glutathione (GSH) in HTR-8/SVneo cells by upregulating the expression of GDF15, inhibiting reactive oxygen species (ROS) accumulation, and increasing mitochondrial membrane potential, thus suppressing apoptosis during oxidative stress. In conclusion, melatonin promotes EMT in trophoblast cells via GDF15-SMAD2/3 pathway and partially induces the expression of GPX4 through GDF15 to enhance oxidative damage resistance in trophoblast cells. These findings highlight melatonin’s regulatory role in embryo implantation and suggest new avenues for exploring its biological effects in reproduction and clinical applications.
Anionic lipids direct efficient microfluidic encapsulation of stable and functionally active proteins in lipid nanoparticles
Because proteins do not efficiently pass through the plasma membrane, protein therapeutics are limited to target ligands located at the cell surface or in serum. Lipid nanoparticles can facilitate delivery of polar molecules across a membrane. We hypothesized that because most proteins are amphoteric ionizable polycations, proteins would associate with anionic lipids, enabling microfluidic chip assembly of stable EP-LNPs (Encapsulated Proteins in Lipid NanoParticles). Here, by employing anionic lipids we were able to efficiently load proteins into EP-LNPs at protein:lipid w:w ratios of 1:20. Several proteins with diverse molecular weights and isoelectric points were encapsulated at efficiencies of 70 75%–90% and remained packaged for several months. Proteins packaged in EP-LNPs efficiently entered mammalian cells and fungal cells with cell walls. The proteins delivered intracellularly were functional. EP-LNPs technology should improve cellular delivery of medicinal antibodies, enzymes, peptide antimetabolites, and dominant negative proteins, opening new fields of protein therapeutics
Chromosomal 3p loss and 8q gain drive vasculogenic mimicry via HIF-2α and VE-cadherin activation in uveal melanoma
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and is where Vasculogenic Mimicry (VM) was first described. VM enables aggressive cancer cells to independently form blood networks, complicating treatment for patients exhibiting VM. Previous studies linked VE-Cadherin phosphorylation at Y658 to gene expression via Focal Adhesion Kinase (FAK), enhancing the Kaiso/β-catenin/TCF-4 complex associated with VE-Cadherin and thereby promoting VM. Recently, an allosteric HIF-2α inhibitor (Belzutifan) was FDA-approved for VHL-associated ccRCCs. In this research, we elucidate the primary causes of VM formation in UM patients with chromosome 3p loss and chromosome 8q gain, identifying VHL, BAP1, and FAK as important factors driving VM and worsening prognosis. These factors promote abnormal activation of HIF-2α and VE-Cadherin under basal hypoxic conditions, leading to VM formation. Cytoscan 750k experiments on the MUM 2B cell line reveal a loss of chromosome 3p, where the VHL, BAP1, and CTNNB1 genes are located, and a gain of chromosome 8q (FAK), whereas the MUM 2C cell line shows a gain of chromosome 3p. This provides an outstanding cross-sectional model from patient samples to established cell lines for VM studies. LC-MS experiments demonstrate that VE-Cad/ENG expression is related to FAK activity in UM cell lines. Finally, using a combination of Belzutifan (HIF-2α inhibitor) and FAK inhibitor (FAKi), we observed a significant reduction in UM xenografts. Our results lead us to propose combining Belzutifan and FAKi as a personalized treatment strategy for UM patients. This approach inhibits VM formation and counters the initial hypoxic conditions resulting from chromosome 3p loss and chromosome 8q gain in UM patients, instilling confidence in the potential of this treatment strategy.
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