STING deficiency alleviates ferroptosis through FPN1 stabilization in diabetic kidney disease

• Published in: Biochemical pharmacology Vol. 222; p. 116102
• Main Authors: Zhao, Qin-xiao, Yan, Sen-bo, Wang, Fen, Li, Xiao-xing, Shang, Guo-kai, Zheng, Zi-jie, Xiao, Jie, Lin, Zong-wei, Li, Chuan-bao, Ji, Xiao-ping
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.04.2024
• Subjects: Diabetic kidney disease; Ferroptosis; FPN1; Oxidative stress; STING; ESRD; DHE; Oxidative stress; T2DM; KIM1; NAFLD; Scr; PAS; BG; LDL-C; HFD; Ferroptosis; MDA; WB; FPN1; UB; SD; CHX; IB; BUN; DKD; GSH; WT; Diabetic kidney disease; SR; PBS; GPX4; siFPN1; IP; IPITT; xCT; IPGTT; H3; ECM; NCD; TC; DCFH-DA; TG; IRF3; TFR1; ROS; STING; RTECs; FTH; HE
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116102

[Display omitted] Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, has known as one of the most significant pathological processes involved in diabetic kidney disease (DKD). Stimulator of interferon genes (STING) has been demonstrated its potential in regulating ferroptosis, but the regulatory role in DKD mice and underlying mechanisms haven’t been illustrated. To elucidate whether and how STING regulates ferroptosis in DKD, we detected the influence of STING on diabetic-related ferroptosis in a diabetic model and in erastin-induced renal tubular epithelial cells (RTECs). Our study demonstrated that STING was abnormally activated and promoted ferroptosis in DKD. STING deficiency alleviated renal pathologic damages and disfunction in diabetic mice via alleviating ferroptosis and reducing oxidative stress. Mechanismly, STING inhibition was shown to improve ferroptosis and reduce oxidative stress in erastin-induced RTECs. The disruption of ferroportin1 (FPN1) on the basis of STING inhibition abolished the improvements in ferroptosis and promoted reactive oxygen species (ROS) generation. Further, STING inhibition alleviated ferroptosis via stabilizing FPN1 protein level by decreasing ubiquitinated FPN1 for proteasomal degradation. In conclusion, STING deficiency protected against diabetic renal injury via alleviating ferroptosis through stabilizing FPN1 and reducing oxidative stress, providing a possible potential approach for the treatment of DKD.