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

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

doi:10.64898/2026.02.09.704912

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bioRxiv · 10.64898/2026.02.09.704912

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

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Abstract

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 xc- 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, this gene rewiring is associated with reduced levels of redox-active iron and diminished lipid peroxidation, consistent with ferroptosis suppression. These findings suggest that miR-940 coordinates ferroptosis inhibition, which presents a novel regulatory layer for therapeutic exploration in susceptible cancers.

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Kolak, A., Tschuck, J., Weiss, S. A., Kaemena, D., Klimm, K., Galhoz, A., Ringelstetter, L., Fennell, M., Merl-Pham, J., Artati, A., Strasser, S., Garippa, R., Witting, M., Zischka, H., Schick, J. A., Hauck, S. M., Menden, M. P., Vincendeau, M., Stockwell, B. R., Hadian, K.. 2026-02-11. miR-940 suppresses ferroptosis by controlling expression of key regulatory genes. https://doi.org/10.64898/2026.02.09.704912

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