Restoration of Nrf2 Signaling Normalizes the Regenerative Niche

Area of Science:

• Biomedical Science
• Molecular Biology
• Regenerative Medicine

Background:

• Chronic hyperglycemia in diabetes mellitus disrupts cellular redox homeostasis.
• The Keap1/Nrf2 pathway is crucial for regulating the body's antioxidant response.
• Dysfunction of this pathway is linked to various pathological conditions.

Purpose of the Study:

• To investigate the impact of chronic hyperglycemia on the Keap1/Nrf2 pathway in diabetic cutaneous wound healing.
• To assess the potential of targeting Keap1 to restore redox balance and enhance diabetic tissue regeneration.

Main Methods:

• Utilized a diabetic cutaneous wound regeneration model.
• Assessed reactive oxygen species (ROS) production and antioxidant gene expression.
• Employed Western blotting to analyze Nrf2 signaling.
• Developed and tested a topical small interfering RNA (siRNA) therapy targeting Keap1 (siKeap1).

Main Results:

• Chronic hyperglycemia inhibited nuclear translocation of Nrf2 and antioxidant gene activation, leading to ROS accumulation.
• Keap1 inhibition (in vitro and in vivo) restored Nrf2 nuclear translocation, boosted antioxidant gene expression, and normalized ROS levels.
• Topical siKeap1 therapy significantly improved diabetic wound healing and accelerated closure.

Conclusions:

• Chronic hyperglycemia compromises the endogenous antioxidant response, causing redox dysregulation in diabetic tissues.
• Keap1 inhibition effectively restores redox homeostasis and enhances diabetic cutaneous regeneration.
• siRNA-based therapy targeting Keap1 offers a promising strategy for treating diabetic wound complications.