ZMAT3 alleviates cell death in Fanconi anemia via adaptation of sphingolipid metabolism.

Authors

Maeva Loock, Blandine Lucchini, Emmanuelle Latour, Margot Tissandier, Marie Lhomme, Maharajah Ponnaiah, Lucie Hernandez, Loic Maillard, Jean Soulier, Olivier Bluteau, Camille Lobry, Marie-Laure Arcangeli, Wilfried Le Goff, Dominique Bluteau

Published in

Science advances. Volume 12. Issue 31. Pages eaeb6444. Jul 31, 2026. Epub Jul 31, 2026.

Abstract

Fanconi anemia (FA) is characterized by defective DNA repair and chronic p53 activation, predisposing to acute myeloid leukemia through persistent genomic instability. The molecular adaptations enabling cell survival under chronic stress remain poorly understood. This study investigates the role of ZMAT3, a p53 responsive RNA binding protein overexpressed in FA deficient cells, to elucidate its role in cellular adaptation. Using FA patient fibroblasts and Fancg KO mouse models, we launched transcriptomic profiling, lipidomic, and functional analyses. RNA-seq and lipidomic analyses revealed unexpected alterations in sphingolipid metabolism upon ZMAT3 depletion, linked to ceramide accumulation and downregulation of ASAH1 (acid ceramidase). Functionally, ZMAT3 depletion increased DNA damage and enhanced ferroptosis susceptibility, an iron dependent cell death mechanism. Mechanistically, our results showed that ZMAT3 promotes ASAH1 expression, limits ceramide accumulation and protects cells from ferroptosis induced death which could participate to preleukemic clonal evolution and pointing to areas for further exploration in FA-associated malignancies.

PMID:
42536749
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.

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