Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Language: Английский

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Iron, Oxidative Stress, and Metabolic Dysfunction—Associated Steatotic Liver Disease

Antioxidants, Journal Year: 2024, Volume and Issue: 13(2), P. 208 - 208

Published: Feb. 7, 2024

Excess free iron is a substrate for the formation of reactive oxygen species (ROS), thereby augmenting oxidative stress. Oxidative stress well-established cause organ damage in liver, main site storage. Ferroptosis, an iron-dependent mechanism regulated cell death, has recently been gaining attention development and progression liver disease. We therefore summarize mechanisms metabolism, its close connection to ferroptosis, particular relevance disease metabolic-dysfunction-associated fatty potential targets therapy from clinical perspective.

Language: Английский

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Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review)

Molecular Medicine Reports, Journal Year: 2024, Volume and Issue: 29(5)

Published: March 11, 2024

Cardiovascular diseases are caused by pathological cardiac remodeling, which involves fibrosis, inflammation and cell dysfunction. This includes autophagy, apoptosis, oxidative stress, mitochondrial dysfunction, changes in energy metabolism, angiogenesis dysregulation of signaling pathways. These heart structure and/or function ultimately result failure. In an effort to prevent this, multiple cardiovascular outcome trials have demonstrated the benefits sodium‑glucose cotransporter type 2 inhibitors (SGLT2is), hypoglycemic drugs initially designed treat diabetes mellitus. SGLT2is include empagliflozin dapagliflozin, listed as guideline 2021 European Guidelines for Heart Failure 2022 American Association/American College Cardiology/Heart Society America Management. recent years, studies using animal models explored mechanisms remodeling. article reviews role remodeling induced different etiologies provide a further evaluation underlying inhibition SGLT2is, well development novel drug targets.

Language: Английский

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Evaluating the Potential of Quantitative Susceptibility Mapping for Detecting Iron Deposition of Renal Fibrosis in a Rabbit Model

Journal of Magnetic Resonance Imaging, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Background As ferroptosis is a key factor in renal fibrosis (RF), iron deposition monitoring may help evaluating RF. The capability of quantitative susceptibility mapping (QSM) for detecting RF remains uncertain. Purpose To investigate the potential QSM to detect Study Type Animal model. Model Eighty New Zealand rabbits were randomly divided into control (N = 10) and 70) groups, consisting baseline, 7, 14, 21, 28 days 12 each), longitudinal subgroups. was induced via unilateral arteria stenosis. Field Strength/Sequence 3 T, with gradient echo, arterial spin labeling echo. Assessment Bilateral kidney values ( χ ) cortex CO outer medulla OM evaluated histopathology. Statistical Tests Analysis variance, Kruskal–Wallis, Spearman's correlation, area under receiver operating characteristic curve (AUC). P < 0.05 significant. Results In fibrotic kidneys, decreased at 7 ([−6.69 ± 0.98] × 10 −2 ppm) increased during 14–28 ([−1.85 2.11], [0.14 0.58], [1.99 0.60] ppm, respectively), while had opposite trend. Both significantly correlated histopathology (| r | 0.674–0.849). AUC distinguishing degrees 0.692–0.993. contralateral initially ([−6.67 0.84] then recovered baseline ([−4.81 0.89] ppm), 7–28 ([2.58 1.40], [2.25 1.83], [2.49 [2.43 1.32] respectively) higher than ([0.54 0.18] ppm). Data Conclusion Different patterns observed values, suggesting Plain Language Summary Renal (RF) common outcome most diseases, leading scarring loss function. Increasing evidence suggests that abnormal metabolism plays an important role This study used technique called measure levels Specifically, advanced exhibited concentrations, moderate strong correlations between demonstrated could accurately changes assess severity. Overall, shows promise as tool progression. Evidence Level 2 Technical Efficacy Stage

Language: Английский

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Emerging roles of ferroptosis in pulmonary fibrosis: current perspectives, opportunities and challenges

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: June 24, 2024

Abstract Pulmonary fibrosis (PF) is a chronic interstitial lung disorder characterized by abnormal myofibroblast activation, accumulation of extracellular matrix (ECM), and thickening fibrotic alveolar walls, resulting in deteriorated function. PF initiated dysregulated wound healing processes triggered factors such as excessive inflammation, oxidative stress, coronavirus disease (COVID-19). Despite advancements understanding the disease’s pathogenesis, effective preventive therapeutic interventions are currently lacking. Ferroptosis, an iron-dependent regulated cell death (RCD) mechanism involving lipid peroxidation glutathione (GSH) depletion, exhibits unique features distinct from other RCD forms (e.g., apoptosis, necrosis, pyroptosis). Imbalance between reactive oxygen species (ROS) production detoxification leads to ferroptosis, causing cellular dysfunction through peroxidation, protein modifications, DNA damage. Emerging evidence points crucial role ferroptosis progression, driving macrophage polarization, fibroblast proliferation, ECM deposition, ultimately contributing tissue scarring. This review provides comprehensive overview latest findings on involvement signaling mechanisms emphasizing potential novel anti-fibrotic approaches targeting for management.

Language: Английский

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S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells suppress ferroptosis and alleviate radiation-induced lung injury and long-term pulmonary fibrosis

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: Oct. 26, 2024

Radiation-induced lung injury (RILI) is associated with alveolar epithelial cell death and secondary fibrosis in injured lung. Mesenchymal stem (MSC)-derived exosomes have regenerative effect against the potential to intervene of RILI. However, their intervention efficacy limited because they lack targeting characters do not carry sufficient specific effectors. SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S-RBD) binds angiotensin-converting enzyme 2 (ACE2) receptor mediates interaction host cells. MiR-486-5p a multifunctional miRNA angiogenic antifibrotic acts as an effector MSC-derived exosomes. Ferroptosis form radiation injury, its roles mechanisms RILI remain unclear. In this study, we developed engineered SARS-CoV-2-S-RBD- miR-486-5p- modification investigated effects on RIPF action via suppression ferroptosis. Adenovirus-mediated gene led miR-486-5p overexpression human umbilical cord MSC (p < 0.05), thereby constructing (miR-486-MSC-Exo). MiR-486-MSC-Exo promoted proliferation migration irradiated mouse (MLE-12) cells vitro inhibited vivo (all p 0.05). suppressed ferroptosis MLE-12 cells, assay revealed that expression fibrosis-related genes up-regulated following (both reversed induced by TGF-β1 improved pathological mice SARS-CoV-2-S-RBD-modified miR-486-5p-engineered (miR-486-RBD-MSC-Exo) were also constructed, distribution DiR dye-labeled miR-486-RBD-MSC-Exo hACE2CKI/CKI Sftpc-Cre+ demonstrated long-term retention MiR-486-RBD-MSC-Exo significantly survival rate changes Furthermore, miR-486-MSC-Exo exerted anti-fibrotic targeted SMAD2 inhibition Akt phosphorylation activation Engineered miR-486-5p-modification developed. vitro, alleviated ACE2 humanized vivo. activation. This study provides approach for intervention.

Language: Английский

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Ferroptosis in pulmonary fibrosis: an emerging therapeutic target

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 17, 2023

In recent years, the role of ferroptosis in pulmonary fibrosis has garnered increasing interest as a potential therapeutic target. Pulmonary is pathological process characterized by accumulation extracellular matrix affected lung tissues, and currently, there are no effective therapies for preventing or reversing fibrotic lesions. Ferroptosis form programmed cell death that regulated network enzymes signaling pathways. Dysregulation been implicated several diseases, including fibrosis. The lipid peroxides course causes damage to membranes other cellular components, leading ultimately death. Relevant targets intervention include key enzymes, such glutathione peroxidase 4, transcription factors like nuclear factor erythroid 2-related 2, iron chelation. This review provides an overview emerging highlights this pathway. Further research needed develop safe approaches targeting treatment

Language: Английский

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Ferroptosis in diabetic cardiomyopathy: Advances in cardiac fibroblast-cardiomyocyte interactions

Heliyon, Journal Year: 2024, Volume and Issue: 10(15), P. e35219 - e35219

Published: July 28, 2024

Diabetic cardiomyopathy (DCM) is a common complication of diabetes, and its pathogenesis remains elusive. Ferroptosis, process dependent on iron-mediated cell death, plays crucial role in DCM via disrupted iron metabolism, lipid peroxidation, weakened antioxidant defenses. Hyperglycemia, oxidative stress, inflammation may exacerbate ferroptosis diabetes. This review emphasizes the interaction between cardiac fibroblasts cardiomyocytes DCM, influencing occurrence. By exploring modulation for potential therapeutic targets, this article offers fresh perspective treatment. The study systematically covers interplay, mechanisms, targeted drugs linked to development.

Language: Английский

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Identification of early genes in the pathophysiology of fibrotic interstitial lung disease in a new model of pulmonary fibrosis

Cellular and Molecular Life Sciences, Journal Year: 2025, Volume and Issue: 82(1)

Published: March 13, 2025

Some interstitial lung diseases involve pulmonary fibrosis, which is a process that characterized by the excessive and abnormal accumulation of extracellular matrix in interalveolar space. Although current anti-fibrotic therapy aims at slowing down progression it does not reverse it, many drugs were identified basic-research studies failed clinical phases, mainly because lack model can recapitulate pathophysiological mechanisms human fibrosis. We developed novel experimental fibrosis induced cocktail molecules on an air/liquid interface culture mouse embryonic explants. Histological analyses revealed pattern usual pneumonia, worst-prognosis form performed transcriptomics analysis single-cell level after induction before any histological signs could be observed. The results increased expression several gene families are involved early inflammation, iron homeostasis, as well potential new genetic targets.

Language: Английский

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The U-Shaped Association Between Serum Ferritin Levels and Frailty Risk in Older Adults: A Nationwide Population-Based Study (Preprint)

Published: March 2, 2025

Ferritin, a key iron storage protein in the body, acts as an essential indicator of metabolism and is involved various health conditions beyond hematologic disorders. Clinical evidence suggests that both elevated reduced blood ferritin levels correlate with adverse outcomes. To elucidate role circulating potential biomarker for frailty, which reflects overall status biological age, we investigated association between serum concentrations frailty index (FI) community-dwelling older adults. We performed population-based, cross-sectional analysis using data from Korea National Health Nutrition Examination Survey. The study included 6,722 participants aged 65 years older. A deficit accumulation FI was developed 36 items covering physical, cognitive, psychological, social domains. Based on FI, were classified non-frail (FI ≤ 0.15), pre-frail (0.15 < 0.25), or frail > 0.25). Serum measured immunoradiometric assay. When divided into four groups according to concentration quartiles, women men exhibited U-shaped curve, lowest values occurring third quartile (Q3). Consequently, differences among analyzed Q3 reference. In women, significantly higher (Q1) highest (Q4) compared (P 0.001 0.001, respectively). Consistently, Q1 Q4 had odds ratios those Q3, at 2.03 1.35 times, respectively 0.049, Although similar trend noted men, not statistically significant women. Our identified nationally representative cohort. Both low high associated increased risk this relationship being more pronounced than men. This pioneering investigation underscores ferritin, widely used clinical practice, predictive

Language: Английский

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