Autophagy induced by mechanical stress sensitizes cells to ferroptosis by NCOA4-FTH1 axis
Chenyu Luo, Haisheng Liang, Mintao Ji, Caiyong Ye, Yiping Lin, Yuhan Guo, Zhisen Zhang, Zhisen Zhang, Yinyin Shu, Xiaoni Jin, Shuangshuang Lu, Wanling Lu, Yazheng Dang, Hong Zhang, Bingyan Li, Guangming Zhou, Zengli Zhang, Zengli Zhang, Lei Chang
Abstract
Ferroptosis is an iron-dependent regulated form of cell death implicated in various diseases, including cancers, with its progression influenced by iron-dependent peroxidation of phospholipids and dysregulation of the redox system. Whereas the extracellular matrix of tumors provides mechanical cues influencing tumor initiation and progression, its impact on ferroptosis and its mechanisms remains largely unexplored. In this study, we reveal that heightened mechanical tension sensitizes cells to ferroptosis, whereas decreased mechanics confers resistance. Mechanistically, reduced mechanical tension reduces intracellular free iron levels by enhancing FTH1 protein expression. Additionally, low mechanics significantly diminishes NCOA4, pivotal in mediating FTH1 phase separation-induced ferritinophagy. Targeting NCOA4 effectively rescues ferroptosis susceptibility under low mechanical tension through modulation of FTH1 phase separation-driven autophagy. In conclusion, our findings demonstrate that mechanics regulates iron metabolism via NCOA4-FTH1 phase separation-mediated autophagy, thereby influencing ferroptosis sensitivity and offering promising therapeutic avenues for future exploration.