Thalidomide Synergistically Regulates Cell Cycle and Endoplasmic Reticulum Stress to Alleviate RPE Oxidative Damage...

Area of Science:

• Ophthalmology
• Cell Biology
• Pharmacology

Background:

• Dry age-related macular degeneration (AMD) involves retinal pigment epithelium (RPE) degeneration, with limited treatment options.
• Thalidomide has anti-inflammatory and immunomodulatory effects, suggesting potential therapeutic applications.

Purpose of the Study:

• To investigate thalidomide's efficacy in treating dry AMD by examining its effects on RPE cells.
• To elucidate the molecular mechanisms underlying thalidomide's therapeutic actions in dry AMD.

Main Methods:

• Utilized oxidatively injured RPE cells to assess thalidomide's impact on mitochondrial function, cell cycle, and endoplasmic reticulum (ER) stress.
• Employed mouse models of dry AMD to evaluate thalidomide's effects on retinal structure, RPE degeneration, and visual function.
• Investigated the role of E2F2 and FBXO5 in mediating thalidomide's effects.

Main Results:

• Thalidomide restored mitochondrial function, alleviated G2/M phase cell cycle arrest, and suppressed ER stress in injured RPE cells.
• Thalidomide ameliorated oxidative stress-induced retinal damage and RPE degeneration in mice, leading to improved visual function.
• The drug's effects were linked to E2F2 activation and subsequent regulation of FBXO5 expression.

Conclusions:

• Thalidomide offers a promising therapeutic strategy for dry AMD by targeting RPE cell dysfunction.
• The E2F2-FBXO5 signaling pathway is a key mechanism through which thalidomide regulates cell cycle and ER homeostasis.
• This study identifies thalidomide as a potential drug candidate and highlights a novel therapeutic target for dry AMD prevention and treatment.