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Updated: Jan 7, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

チアゾリジン系化合物はE2F2-FBXO5経路を介してRPEの酸化的損傷を軽減するために細胞周期と小胞体ストレスを相乗的に調節する

Jingya Zhu¹, Xinyue Yu¹, Chaojuan Wen^1,2

¹State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

|December 30, 2025

Abstract:

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.

キーワード:

加齢黄斑変性（AMD）細胞周期小胞体ストレス酸化ストレスチアゾリジン系化合物

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