Ferroptosis: principles and significance in health and disease

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Июнь 6, 2024

Abstract Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic pathway in 2012, ferroptosis has emerged crucial mechanism numerous physiological pathological contexts, leading to significant therapeutic advancements across wide range diseases. This review summarizes the fundamental mechanisms regulatory pathways underlying ferroptosis, including both GPX4-dependent -independent antioxidant mechanisms. Additionally, we examine involvement various conditions, cancer, neurodegenerative diseases, sepsis, ischemia–reperfusion injury, autoimmune disorders, metabolic disorders. Specifically, explore role response chemotherapy, radiotherapy, immunotherapy, nanotherapy, targeted therapy. Furthermore, discuss pharmacological strategies for modulating potential biomarkers monitoring this process. Lastly, elucidate interplay between other forms regulated death. Such insights hold promise advancing our understanding context human health disease.

Язык: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Язык: Английский

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Receptor-ligand interactions for optimized endocytosis in targeted therapies

Journal of Controlled Release, Год журнала: 2025, Номер 380, С. 524 - 538

Опубликована: Фев. 12, 2025

Receptor-mediated endocytosis plays a crucial role in the success of numerous therapies and remains central to advancing drug development. This process begins with ligand binding specific receptors, triggering internalization intracellular trafficking receptor-ligand complexes. These complexes are subsequently directed into distinct routes, either toward lysosomal degradation or recycling cell surface, implications for therapeutic outcomes. review examines interactions as key modulators endocytosis, emphasizing their shaping design efficacy. Advances selecting pairs engineering ligands optimized properties have enabled precise control over internalization, endosomal sorting, trafficking, providing tailored solutions diverse applications. Leveraging these insights, strategies such RNA-based therapies, antibody-drug conjugates (ADCs), targeted protein (TPD) platforms been refined selectively avoid promote degradation, thereby enhancing By bridging fundamental mechanisms receptor-mediated innovative approaches, this offers framework precision medicine.

Язык: Английский

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A Bifunctional Lysosome‐Targeting Chimera Nanoplatform for Tumor‐Selective Protein Degradation and Enhanced Cancer Immunotherapy

Advanced Materials, Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Lysosome-targeting chimeras (LYTACs) have recently emerged as a promising therapeutic strategy for degrading extracellular and membrane-associated pathogenic proteins by hijacking lysosome-targeting receptors. However, the antitumor performance of LYTAC is limited its insufficient tumor accumulation nonspecific activation. Additionally, synergistic effects LYTACs other modalities are crucial. To address these issues, bifunctional nanoplatform (NLTC) developed tumor-selective protein degradation enhanced cancer immunotherapy. By rationally controlling surface composition, NLTC can effectively transport or membrane into lysosomes via cation-independent mannose 6-phosphate With removable modification, an obtained that efficiently accumulated in tissues avoided on-target off-tumor toxicity. Moreover, synthesis method generally applicable to various enzymes. Thus, catalase (CAT) encapsulated with synergistically degrade cell programmed death ligand-1 (PD-L1), relieve immunosuppressive microenvironment effective immunotherapy, significantly inhibit growth, recurrence, metastasis B16F10-bearing mice. This work presents not only perform tissue-selective but also integrate modalities, providing insights design advanced technologies clinical applications.

Язык: Английский

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PROTACs coupled with oligonucleotides to tackle the undruggable

Bioanalysis, Год журнала: 2025, Номер unknown, С. 1 - 16

Опубликована: Фев. 3, 2025

Undruggable targets account for roughly 85% of human disease-related and represent a category therapeutic that are difficult to tackle with traditional methods, but their considerable clinical importance. These generally defined by planar functional interfaces the absence efficient ligand-binding pockets, making them unattainable conventional pharmaceutical strategies. The advent oligonucleotide-based proteolysis-targeting chimeras (PROTACs) has instilled renewed optimism in addressing these challenges. PROTACs facilitate targeted degradation undruggable entities, including transcription factors (TFs) RNA-binding proteins (RBPs), via proteasome-dependent mechanisms, thereby presenting novel approaches diseases linked targets. This review offers an in-depth examination recent progress integration PROTAC technology oligonucleotides target traditionally proteins, emphasizing design principles mechanisms action innovative PROTACs.

Язык: Английский

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GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins

Acta Pharmaceutica Sinica B, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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PCSK9 Targeted Autophagosome-Tethering Compounds: Design, Synthesis, and Antiatherosclerosis Evaluation

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 14, 2025

Atherosclerosis is a multifaceted disease involving various cell types and complex mechanisms, it the main cause of cardiovascular disease. Proprotein convertase subtilisin/kexin type-9 (PCSK9) has been identified as an effective target for treating atherosclerosis; however, most current research focuses on biological drugs. Our work optimized previously reported autophagosome-tethering compound OY3, specifically, W6 induced PCSK9 degradation with 5-fold increase in activity 6-fold bioavailability. Compared to currently marketed drug, siRNA, demonstrated comparable antiatherosclerosis effects both vivo vitro. exhibited beneficial hepatocytes, endothelial cells, macrophages, vascular smooth muscle cells involved atherosclerosis process, making promising potential drug. This highlights feasibility ATTECs degrading intracellular extracellular proteins, our novel PCSK9-ATTEC provides valuable reference treatment atherosclerotic diseases.

Язык: Английский

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Next steps for targeted protein degradation

Cell chemical biology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

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Transforming Therapeutic Approaches with PROTAC Technology: New Targets and Potentials

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(5), С. 573 - 575

Опубликована: Апрель 26, 2024

This Patent Highlight delves into the ground-breaking impact of Proteolysis Targeting Chimeras (PROTACs) on targeted protein degradation, offering novel strategies to eliminate pathogenic proteins. By exploring cutting-edge development compounds targeting IRAK-4 and CDK2, this work illuminates PROTACs' role in treating immune disorders cancer. The analysis not only highlights specificity potential PROTACs transforming disease treatment but also addresses challenges future directions technology, emphasizing its broad applicability promise more effective therapeutic strategies.

Язык: Английский

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A photoactivatable upconverting nanodevice boosts the lysosomal escape of PROTAC degraders for enhanced combination therapy

Biomaterials Science, Год журнала: 2024, Номер 12(14), С. 3686 - 3699

Опубликована: Янв. 1, 2024

A near-infrared light-controlled PROTAC delivery nanodevice achieves enhanced protein degradation efficiency and synergistic therapeutic efficacy in combination with NIR light-triggered photodynamic therapy.

Язык: Английский

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