Small-molecule FTO inhibitor MO-I-500 protects C8-B4 microglial cells from erastin-induced ferroptosis

  • Sci Rep. 2026 Apr 18;16(1):18062. doi: 10.1038/s41598-026-47881-0.
Denise Greco  1 ,  Debanjan Das  2 ,  Jiří Novotný  1 ,  Mark J Olsen  3  4 ,  Petr Telenský  5  6
Affiliations
  • 1. Department of Physiology, Faculty of Science, Charles University, Viničná 1594/7, Prague, 12800, Czech Republic.
  • 2. Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
  • 3. Department of Pharmaceutical Sciences, Midwestern University, Campus Glendale, Glendale, AZ, USA.
  • 4. Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, IL, USA.
  • 5. Department of Physiology, Faculty of Science, Charles University, Viničná 1594/7, Prague, 12800, Czech Republic. [email protected].
  • 6. Dementia Research Group, International Clinical Research Center of St. Anne 's University Hospital Brno, Brno, Czech Republic. [email protected].
PMID: 42000801 DOI: 10.1038/s41598-026-47881-0
Abstract

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and the accumulation of lipid-derived Reactive Oxygen Species (ROS). This process has been implicated in various neurological disorders, highlighting the importance of iron metabolism in brain homeostasis. Emerging evidence suggests that epitranscriptomic regulation, particularly N6-methyladenosine (m6A) RNA methylation, may influence ferroptotic signaling pathways. The fat mass and obesity-associated protein (FTO), an m6A RNA demethylase, has been implicated in cellular stress responses; however, its role in Ferroptosis remains unclear. Here, we show that inhibition of FTO activity attenuates erastin-induced Ferroptosis in C8-B4 microglial cells. Treatment with MO-I-500, a well-characterized FTO inhibitor, significantly decreased erastin-induced cell migration, ROS production, and lipid accumulation. Together, these findings demonstrate that FTO-mediated m6A RNA demethylation plays a crucial role in regulating ferroptotic cell death and suggest that targeting FTO may represent a novel therapeutic strategy for ferroptosis-related neurological disorders.

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