Language：English   Publishing type：Research paper (scientific journal)  

Cellular senescence, a state of irreversible cell cycle arrest, is implicated in age-related diseases. While it is well known that senescent cells resist apoptosis, studies on their resistance to ferroptosis are limited and not fully understood. Senescent cells remain sensitive to ferroptosis induced by direct inhibition of glutathione peroxidase 4 (GPX4) but resist ferroptosis from cystine starvation, suggesting a role for mitochondrial metabolism. Here, we found that this resistance is mediated by peroxisome proliferator-activated receptor α (PPARα)-dependent upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which inactivates pyruvate dehydrogenase (PDH) and suppresses mitochondria-derived reactive oxygen species, a key driver of ferroptosis. Our findings identify the PPARα–PDK4–PDH axis as a metabolic switch regulating ferroptosis sensitivity in senescent cells and provide insight into the senescence–ferroptosis interaction.

DOI： 10.1002/1873-3468.70332

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Drugs in Context  

Background: Oxidative modifications of low-density lipoproteins (LDL) have been reported in patients with β-thalassaemia/haemoglobin E (HbE) and are related to cardiovascular complications. Deferiprone (L1) is an iron chelator that decreases iron overload and, consequently, reduces oxidative stress. This study assesses the protective effect of L1 on the oxidative status of LDL in patients with β-thalassaemia/HbE.

Methods: Twenty-nine patients with β-thalassaemia/ HbE treated with L1 were recruited. The study included a 4-week washout period followed by 4 and 12 weeks of L1 treatment. Non-transferrin-bound iron (NTBI) levels and oxidative stress markers, including thiobarbituric acid reactive substances and α-tocopherol, were monitored at each visit. The rate and content of lipid radical formation following Cu2+-induced LDL oxidation in vitro were detected by NBD-Pen, a specific fluorescence probe.

Results: L1 was shown to prevent the depletion of α-tocopherol, decrease thiobarbituric acid reactive substances and preserve the levels of lipid components in LDL. A negative correlation between serum NTBI and LDL α-tocopherol indicated that the circulating non-redox-active NTBI can lead to the depletion of α-tocopherol. LDL from the washout period showed the highest oxidative susceptibility when evaluated by NBD-Pen.

Conclusion: Iron chelation therapy with L1 improves the oxidative status of LDL in patients with β-thalassaemia/HbE.

DOI： 10.7573/dic.2025-7-6

Web of Science

Scopus

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Iron overload results in lipid peroxidation (LPO) and the oxidative modification of circulating lipoproteins, which contributes to cardiovascular complications in patients with β-thalassemia. Investigating LPO may provide opportunities for the development of novel therapeutic strategies; however, the chemical pathways underlying iron overload-induced LPO in β-thalassemia lipoproteins remain unclear. In this study, we identified various species of lipid radicals (L•), the key mediators of LPO, and oxidized cholesteryl esters (oxCE) derived from the in vitro oxidation of major core lipids, cholesteryl linoleate (CE18:2) and cholesteryl arachidonate (CE20:4); the levels of these radical products in low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were measured and compared between β-thalassemia patients and healthy subjects by using a specific fluorescent probe for L• with a liquid chromatography-tandem mass spectrometric method. Our results demonstrated that iron overload substantially decreased the levels of CE18:2 and CE20:4 substrates and α-tocopherol, resulting in higher levels of full-length and short-chain truncated L• and oxCE products. In particular, CE epoxyallyl radicals (•CE-O) were observed in the lipoproteins of β-thalassemia, revealing the pathological roles of iron overload in the progression of LPO. In addition, we found that intermission for two weeks of iron chelators can increase the production of these oxidized products; therefore, suggesting the beneficial effects of iron chelators in preventing LPO progression. In conclusion, our findings partly revealed the primary chemical pathway by which the LPO of circulating lipoproteins is influenced by iron overload and affected by iron chelation therapy. Moreover, we found that •CE + O shows potential as a sensitive biomarker for monitoring LPO in individuals with β-thalassemia.

DOI： 10.1016/j.freeradbiomed.2024.09.026

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.biopha.2022.113624

Event date： 2026.6

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2026.6

Language：English   Presentation type：Oral presentation (general)  

Venue：滋賀   Country：Japan  

Event date： 2026.6

Language：English   Presentation type：Oral presentation (general)  

Venue：滋賀   Country：Japan  

Event date： 2025.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：長崎   Country：Japan  

Event date： 2025.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：長崎   Country：Japan