Thalidomide Synergistically Regulates Cell Cycle and Endoplasmic Reticulum Stress to Alleviate RPE Oxidative Damage Through the E2F2-FBXO5 Pathway

Thalidomide, a glutamate derivative with teratogenicity, possesses anti-inflammatory, immunomodulatory, and anti-angiogenic properties that enable its use in treating refractory diseases unresponsive to conventional therapies. Dry age-related macular degeneration (AMD), characterized by retinal pigment epithelium (RPE) degeneration and lacking effective therapies, represents a significant unmet medical need. Our findings demonstrated that thalidomide significantly restores mitochondrial function, alleviates G2/M phase cell cycle arrest, and suppresses sustained endoplasmic reticulum (ER) stress in oxidatively injured RPE cells. Mechanistically, these effects are coordinated through E2F2 activation, which subsequently regulates FBXO5 expression. Moreover, thalidomide was able to ameliorate oxidative stress-induced retinal structural disorders and RPE degeneration, and improve visual function in mice. In summary, this study elucidates that thalidomide synergistically regulates cell cycle progression and endoplasmic reticulum homeostasis through the E2F2-FBXO5 signaling pathway, providing a new drug candidate and therapeutic target for the prevention and treatment of dry AMD. Graphical Schematic diagram of the cytoprotective mechanism of thalidomide in RPE cells. Thalidomide activates the transcription factor E2F2, which upregulates FBXO5 expression. This E2F2-FBXO5 pathway coordinately alleviates G2/M phase cell cycle arrest, restores mitochondrial function, and suppresses endoplasmic reticulum stress, thereby protecting RPE cells from oxidative damage.