Theaflavin-3,3'-digallate alleviates glucolipotoxicity-induced insulin secretion dysfunction in pancreaticβ-TC-6 cells and zebrafish via anti-ferroptotic mechanisms by activating SERCA2  

作　　者：Kaixi Wang Huanqing Zhu Jiaxin Kang Shuna Chen Puming He Youying Tu Bo Li 

机构地区：[1]Department of Tea Science,College of Agriculture and Biotechnology,Zhejiang University,Hangzhou 310058,China

出　　处：《Food Science and Human Wellness》2025年第4期1498-1513,共16页食品科学与人类健康(英文)

基　　金：supported by National Natural Science Foundation of China(32272303);Natural Science Foundation of Zhejiang Province,China(LY21C200010)。

摘　　要：Theaflavins from black tea effectively improve insulin secretion in obesity and diabetes,but the molecular mechanisms are unclear.Here,the palmitic acid(PA)-induced pancreaticβ-TC-6 cells and high fat-/high glucose-induced zebrafish were used.The effects of theaflavin-3,3'-digallate(TF3)on glucolipotoxicityinduced insulin secretion dysfunction,ferroptosis and endoplasmic reticulum(ER)stress were investigated by a variety of molecular biological approaches,inductively coupled plasma-mass spectrometry(ICP-MS),transmission electron microscopy(TEM)and widely targeted metabolomics analysis.TF3 was found to potently inhibit glucolipotoxicity-induced insulin secretion dysfunction and ferroptosis inβ-TC-6 cells and zebrafish,with increasing glutathione peroxidase 4(GPX4)expression,suppressing lipid peroxidation and iron accumulation and protecting mitochondria.Additionally,TF3 attenuated ER stress by regulating 3 unfolded protein response(UPR)pathways inβ-TC-6 cells,and significantly modulated linoleic acid metabolism and L-kynurenine signalling in zebrafish.The expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2(SERCA2)was obviously enhanced by TF3.Thapsigargin,a SERCA2 inhibitor,remarkably reversed the effects of TF3 on insulin production,ferroptosis,ER stress and the kynurenine signalling.Together,this work revealed the critical role of SERCA2 in ferroptosis regulation,and demonstrated TF3 targeted SERCA2 to inhibit ER stress and ferropto sis,thereby protectingβ-cell secretory function from glucolipotoxicity.

关 键 词：Theaflavin-3 3'-digallate Pancreaticβ-cells Ferroptosis Endoplasmic reticulum stress Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 

分 类 号：R587.2[医药卫生—内分泌] R556.3[医药卫生—内科学]