Get started
Work

MAFF regulates ferroptotic sensitivity through iron homeostasis and fatty acid synthesis

Year: 2026
Type: article
Abstract: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. In this study, we identify the transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a key regulator that promotes breast cancer progression while simultaneously sensitizing tumor cells to ferroptosis. Integrated RNA-sequencing and chromatin immunoprecipitation (ChIP)-sequencing revealed that MAFF directly regulates genes involved in iron and fatty acid metabolism. MAFF enhances intracellular iron availability by transactivating SLC11A2 and NCOA4, expanding the labile iron pool essential for ferroptotic signaling. In parallel, MAFF represses CPT2, FASN, and SCD1, reprogramming lipid metabolism to favor the accumulation of polyunsaturated fatty acids (PUFAs) over monounsaturated fatty acids (MUFAs), thereby increasing lipid peroxidation susceptibility. These alterations reduce triglyceride (TG) levels and lipid droplet (LD) formation following ferroptosis induction. Functionally, MAFF-mediated repression of CPT2 diminishes fatty acid oxidation and enhances tumor invasion, underscoring a dual role whereby MAFF drives tumor progression yet primes cells for ferroptotic death. Collectively, our study identifies MAFF as a transcriptional switch linking iron homeostasis and lipid metabolism to ferroptotic vulnerability, highlighting its potential as a biomarker and therapeutic target in basal-like breast cancer.
DOI: 10.1038/s41419-026-08885-w
Authors: Nuria Vilaplana Lopera, Jiyoung Kim, Pei Ju Lee, Maxime Dubail, Shuhei Aramaki, Maria Jerome, Adela Valentova, Tianxu Hou, Haowen Jiang, Stephano Spano Mello, Eun-Woo Lee, Christian Babbs, Theo Rich, Yu Xu, Yanyan Jiang, Charles Fouillade, Mitsutoshi Setou, Jiangbin Ye, Eui Jung Moon
Institutions: University of Oxford, Yonsei University, Yonsei Cancer Hospital, Hamamatsu University School of Medicine, Hamamatsu University, Stanford Medicine, Stanford University, University of Rochester Medicine, University of Rochester, Korea Research Institute of Bioscience and Biotechnology, Sungkyunkwan University, Korea University of Science and Technology, John Radcliffe Hospital, MRC Weatherall Institute of Molecular Medicine, Centre National de la Recherche Scientifique, Inserm, Université Paris Sciences et Lettres, Université Paris-Saclay, Imagerie, Radiothérapie Innovante et médecine des Systèmes, Institut Curie, Hainan Medical University
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $4,990
OpenAlex ID: W7162697898
FWCI:
Cites:
Cited by:
Related to: