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Kolak, A. ; Tschuck, J. ; Weiss, S.A. ; Kaemena, D.F. ; Klimm, K. ; Galhoz, A. ; Ringelstetter, L. ; Fennell, M.* ; Merl-Pham, J. ; Artati, A. ; Strasser, S. ; Garippa, R.* ; Witting, M. ; Zischka, H. ; Schick, J. ; Hauck, S.M. ; Menden, M.P. ; Vincendeau, M. ; Stockwell, B.R.* ; Hadian, K.

miR-940 suppresses ferroptosis by controlling expression of key regulatory genes.

Adv. Sci.:e75830 (2026)

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Ferroptosis is a form of regulated cell death that is characterized by iron-dependent lipid peroxidation. This process is regulated by specific metabolites, the lipid composition of the cells, redox-active iron, and antioxidant mechanisms. Although numerous regulators have been identified over the past decade, exploring other mechanisms, particularly from non-coding genomic regions, can build a thorough understanding of the multifaceted regulatory processes underlying ferroptosis. MicroRNAs (miRNAs) play a crucial role in gene regulation and cellular functions. Through a CRISPR KO screen, we identified miR-940 as a negative regulator of ferroptosis. Overexpression of miR-940 in several cell lines consistently suppressed ferroptosis induced by system x_c ^- inhibition. Notably, multiple cancer patient cohorts with elevated miR-940 levels exhibit reduced survival. Integrated bioinformatic, transcriptomic, and proteomic analyses revealed that miR-940 decreases the expression of ACSL4, LPCAT3, DMT1, and NCOA4, and simultaneously increases levels of GPX4. Pharmacological inhibition of GPX4 attenuated the protective effect of miR-940, indicating that its primary anti-ferroptotic activity is mediated through GPX4. Overall, these mechanistic insights link gene rewiring to reduced levels of redox-active iron and diminished lipid peroxidation, mediating ferroptosis suppression. These findings provide a defined regulatory network, presenting a novel target for therapeutic exploration in susceptible cancers.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Regulator ; Microrna ; Regulation Of Gene Expression ; Gene ; Gpx4 ; Regulator Gene ; Gene Expression ; Programmed Cell Death ; Cell; Epithelial-mesenchymal Transition; Computational Platform; Cell Invasion; Proliferation; Metastasis; Carcinoma

ISSN (print) / ISBN 2198-3844

e-ISSN 2198-3844

Journal Advanced science

Quellenangaben Article Number: e75830

Publisher Wiley

Publishing Place Weinheim

Reviewing status Peer reviewed

Institute(s) Research Unit Signaling and Translation (SAT)
Institute of Virology (VIRO)
Institute of Computational Biology (ICB)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Molecular Toxicology and Pharmacology (TOX)

Grants Columbia University Digestive and Liver Disease Research Center
NIH/NCI Cancer Center Support
National Science Foundation
Molecular Pathology Shared Resource
NIH Shared Instrumentation
Deutsche Forschungsgemeinschaft