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Cullin-3 and Regulatory Biomolecules Profiling in Vitiligo: Integrated Docking, Clinical, and In Silico Insights
Hidi A A Abdellatif1,2,3, Mohamed Azab4, Eman Hassan El-Sayed5
1Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
Background:
Vitiligo, a chronic depigmentation disorder driven by oxidative stress and immune dysregulation, remains poorly understood mechanistically. The Keap1/NRF2/ARE pathway is critical for melanocyte protection against oxidative damage; however, the role of Cullin-3 (CUL3), a scaffold for E3 ubiquitin ligases that regulate NRF2 degradation, and its interplay with inflammatory mediators in vitiligo pathogenesis are underexplored. This study investigates CUL3, NRF2, and the associated regulatory networks in vitiligo, integrating clinical profiling and computational docking to identify therapeutic targets.
Methods:
A case-control study compared non-segmental vitiligo patients with age-/sex-matched controls. Lesional skin biopsies were analyzed by qRT-PCR for the expression of CUL3, NRF2, miRNA-146a, FOXP3, NF-κB, IL-6, TNF-α, and P53. Molecular docking was used to evaluate vitexin's binding affinity to Keap1, validated by root mean square deviation (RMSD) calculations.
Results:
Patients with vitiligo exhibited significant downregulation of CUL3 (0.27 ± 0.03 vs. 1 ± 0.58; p = 0.013), NRF2 (0.37 ± 0.26 vs. 1 ± 0.8; p = 0.001), and FOXP3 (0.09 ± 0.2 vs. 1 ± 0.3; p = 0.001), alongside the upregulation of miRNA-146a (4.7 ± 1.9 vs. 1 ± 0.8; p = 0.001), NF-κB (4.7 ± 1.9 vs. 1 ± 0.5; p = 0.001), IL-6 (2.8 ± 1.5 vs. 1 ± 0.4; p = 0.001), and TNF-α (2.2 ± 1.1 vs. 1 ± 0.3; p = 0.001). P53 showed no differential expression (p > 0.05). Docking revealed a strong binding of vitexin to Keap1 (RMSD: 0.23 Å), mirroring the binding of the control ligand CDDO-Im.
Conclusions:
Dysregulation of the CUL3/Keap1/NRF2 axis and elevated miRNA-146a levels correlate with vitiligo progression, suggesting a role for oxidative stress and immune imbalance. Vitexin's high-affinity docking to Keap1 positions it as a potential modulator of the NRF2 pathway, offering novel therapeutic avenues. This study highlights the translational potential of targeting the ubiquitin-proteasome and antioxidant pathways in the management of vitiligo.
Insights
Vitiligo involves CUL3/Keap1/NRF2 pathway dysregulation and increased miRNA-146a, linked to oxidative stress. The compound vitexin shows promise for vitiligo treatment by targeting the NRF2 pathway.
Area of Science:
- Dermatology
- Molecular Biology
- Immunology
Background:
- Vitiligo is a chronic depigmentation disorder linked to oxidative stress and immune dysregulation.
- The Keap1/NRF2/ARE pathway is crucial for melanocyte protection, but the role of Cullin-3 (CUL3) in vitiligo is unclear.
- This study explores CUL3, NRF2, and related inflammatory pathways in vitiligo pathogenesis.
Purpose of the Study:
- Investigate the role of CUL3, NRF2, and associated regulatory networks in vitiligo.
- Identify potential therapeutic targets by integrating clinical data and computational analysis.
- Examine the interplay between the CUL3/Keap1/NRF2 axis and inflammatory mediators in vitiligo.
Main Methods:
- A case-control study compared vitiligo patients with healthy controls.
- Quantitative real-time PCR (qRT-PCR) analyzed gene and miRNA expression in skin biopsies.
- Molecular docking evaluated vitexin's binding affinity to Keap1.
Main Results:
- Vitiligo patients showed decreased expression of CUL3, NRF2, and FOXP3.
- Elevated levels of miRNA-146a, NF-κB, IL-6, and TNF-α were observed in vitiligo patients.
- Molecular docking demonstrated strong binding of vitexin to Keap1.
Conclusions:
- CUL3/Keap1/NRF2 axis dysregulation and increased miRNA-146a correlate with vitiligo progression.
- Vitexin's interaction with Keap1 suggests potential for modulating the NRF2 pathway in vitiligo.
- Targeting the ubiquitin-proteasome and antioxidant pathways offers therapeutic potential for vitiligo management.
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