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. 2025 Jun;21(6):1263-1282.
doi: 10.1080/15548627.2025.2469129. Epub 2025 Mar 10.

Autophagy induced by mechanical stress sensitizes cells to ferroptosis by NCOA4-FTH1 axis

Chenyu Luo  1   2 , Haisheng Liang  1 , Mintao Ji  1 , Caiyong Ye  1 , Yiping Lin  1 , Yuhan Guo  1 , Zhisen Zhang  1 , Yinyin Shu  1 , Xiaoni Jin  1 , Shuangshuang Lu  1 , Wanling Lu  2 , Yazheng Dang  2 , Hong Zhang  3 , Bingyan Li  4 , Guangming Zhou  1 , Zengli Zhang  4 , Lei Chang  1   5
Affiliations

Autophagy induced by mechanical stress sensitizes cells to ferroptosis by NCOA4-FTH1 axis

Chenyu Luo et al. Autophagy. 2025 Jun.

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.Abbreviations: ACO1: aconitase 1; ATG5: autophagy related 5; DMSO: dimethyl sulfoxide; EGFP: enhanced green fluorescent protein; FACS: fluorescence-activated cell sorting; FER-1: ferrostatin-1; FTH1: ferritin heavy chain 1; FTL: ferritin light chain; GPX4: glutathione peroxidase 4; IR: ionizing radiation; IREB2: iron responsive element binding protein 2; NCOA4: nuclear receptor coactivator 4; NFE2L2: NFE2 like bZIP transcription factor 2; NOPP: norepinephrine; PBS: phosphate-buffered saline; PI: propidium iodide; RSL3: (1S,3 R)-RSL3; TCGA: The Cancer Genome Atlas; WWTR1: WW domain containing transcription regulator 1; YAP1: Yes1 associated transcriptional regulator.

Keywords: Ferritinophagy; ferroptosis; iron metabolism; mechanotransduction; phase separation.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

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