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CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications.

Zhe GongJinjin ZhuJunxin ChenFan FengHaitao ZhangZheyuan ZhangChenxin SongKaiyu LiangShuhui YangShunwu FanXiang-Qian FangShu-Ying Shen
Published in: Nature communications (2023)
Osteoarthritis is a prevalent age-related disease characterized by dysregulation of extracellular matrix metabolism, lipid metabolism, and upregulation of senescence-associated secretory phenotypes. Herein, we clarify that CircRREB1 is highly expressed in secondary generation chondrocytes and its deficiency can alleviate FASN related senescent phenotypes and osteoarthritis progression. CircRREB1 impedes proteasome-mediated degradation of FASN by inhibiting acetylation-mediated ubiquitination. Meanwhile, CircRREB1 induces RanBP2-mediated SUMOylation of FASN and enhances its protein stability. CircRREB1-FASN axis inhibits FGF18 and FGFR3 mediated PI3K-AKT signal transduction, then increased p21 expression. Intra-articular injection of adenovirus-CircRreb1 reverses the protective effects in CircRreb1 deficiency mice. Further therapeutic interventions could have beneficial effects in identifying CircRREB1 as a potential prognostic and therapeutic target for age-related OA.
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