ZMAT3 alleviates cell death of Fanconi Anemia deficient cells by modulating sphingolipid metabolism and ferroptosis.

Fanconi Anemia (FA) is a genetic disorder marked by bone marrow failure and cancer risk. FA features continuous activation of the p53 pathway, leading to an exacerbated cellular response to stress and DNA damage and significantly altering cellular metabolism. Here, we pointed out for the first time the overexpression of ZMAT3, an RNA-binding protein, in murine FA-deficient hematopoietic cells. To elucidate the functions of ZMAT3 in the context of FA, we employed a two-pronged experimental approach. Initially, hematopoietic stem cells from FA knockout (FA-KO) mice with targeted downregulation of ZMAT3 and a human fibroblast cell line derived from an FA patient. Combining functional and Omics approaches, our study uncovers the critical involvement of ZMAT3 in enhancing the survival of FA-deficient cells by modulating sphingolipid metabolism and ferroptosis. ZMAT3 emerges as a pivotal factor in mitigating hematopoietic stem cell exhaustion during the initial stages of FA.