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Circulatory Indicators of Lipid Peroxidation, the Driver of Ferroptosis, Reflect Differences between
Ljiljana Stojkovic1, Ana Djordjevic1, Milan Stefanovic1
1Laboratory for Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia.
Abstract:
Ferroptosis, a lipid peroxidation- and iron-mediated type of regulated cell death, relates to both neuroinflammation, which is common in relapsing-remitting multiple sclerosis (RRMS), and neurodegeneration, which is prevalent in progressive (P)MS. Currently, findings related to the molecular markers proposed in this paper in patients are scarce. We analyzed circulatory molecular indicators of the main ferroptosis-related processes, comprising lipid peroxidation (malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and hexanoyl-lysine adduct (HEL)), glutathione-related antioxidant defense (total glutathione (reduced (GSH) and oxidized (GSSG)) and glutathione peroxidase 4 (GPX4)), and iron metabolism (iron, transferrin and ferritin) to estimate their contributions to the clinical manifestation of MS and differences between RRMS and PMS disease course. In 153 patients with RRMS and 69 with PMS, plasma/serum lipid peroxidation indicators and glutathione were quantified using ELISA and colorimetric reactions, respectively. Iron serum concentrations were determined using spectrophotometry, and transferrin and ferritin were determined using immunoturbidimetry. Compared to those with RRMS, patients with PMS had decreased 4-HNE (median, 1368.42 vs. 1580.17 pg/mL; p = 0.03). Interactive effects of MS course (RRMS/PMS) and disease-modifying therapy status on MDA (p = 0.009) and HEL (p = 0.02) levels were detected. In addition, the interaction of disease course and self-reported fatigue revealed significant impacts on 4-HNE levels (p = 0.01) and the GSH/GSSG ratio (p = 0.04). The results also show an association of MS course (p = 0.03) and EDSS (p = 0.04) with GSH levels. No significant changes were observed in the serum concentrations of iron metabolism indicators between the two patient groups (p > 0.05). We suggest circulatory 4-HNE as an important parameter related to differences between RRMS and PMS. Significant interactions of MS course and other clinically relevant parameters with changes in redox processes associated with ferroptosis support the further investigation of MS with a larger sample while taking into account both circulatory and central nervous system estimation.
Insights
Circulating 4-hydroxynonenal (4-HNE) levels are lower in progressive multiple sclerosis (PMS) than relapsing-remitting MS (RRMS). These findings highlight ferroptosis markers as potential indicators for MS disease course differences.
Area of Science:
- Biochemistry
- Neuroscience
- Immunology
Background:
- Ferroptosis, a cell death pathway involving lipid peroxidation and iron, is implicated in multiple sclerosis (MS) neuroinflammation and neurodegeneration.
- Understanding molecular markers of ferroptosis in different MS courses (relapsing-remitting MS [RRMS] vs. progressive MS [PMS]) is crucial for clinical insights.
- Current data on ferroptosis-related molecular markers in MS patients are limited.
Purpose of the Study:
- To analyze circulatory molecular indicators of ferroptosis, including lipid peroxidation, glutathione antioxidant defense, and iron metabolism.
- To assess the contribution of these markers to MS clinical manifestations and differentiate between RRMS and PMS.
- To investigate potential interactions between MS disease course, therapy, fatigue, and ferroptosis markers.
Main Methods:
- Quantification of plasma/serum lipid peroxidation markers (MDA, 4-HNE, HEL) and glutathione (GSH, GSSG) using ELISA and colorimetric assays in 153 RRMS and 69 PMS patients.
- Measurement of serum iron, transferrin, and ferritin concentrations via spectrophotometry and immunoturbidimetry.
- Statistical analysis to compare marker levels between RRMS and PMS and explore interactions with clinical parameters.
Main Results:
- Patients with PMS exhibited significantly lower levels of 4-hydroxynonenal (4-HNE) compared to RRMS patients (p=0.03).
- Significant interactions were found between MS disease course and disease-modifying therapy status affecting MDA and HEL levels.
- Interactions between disease course and fatigue impacted 4-HNE levels and the GSH/GSSG ratio, while MS course and EDSS correlated with GSH levels.
Conclusions:
- Circulatory 4-HNE may serve as a key indicator differentiating between RRMS and PMS.
- Interactions involving MS disease course, therapy, fatigue, and redox processes suggest ferroptosis pathways are dynamically linked to clinical MS features.
- Further investigation with larger cohorts is warranted to explore ferroptosis markers in both circulation and the central nervous system for a comprehensive understanding of MS.
