Irf4 participates in benzene-induced hematopoietic senescence through mitochondrial ROS-dependent BCAA catabolism

The continuous accumulation of senescent hematopoietic stem progenitors (HSPCs) contributes to hematopoietic damage. Benzene is a confirmed human carcinogen, and its damage to HSPCs is a key event in benzene poisoning. However, whether the environmental dose of benzene is involved in HSPC damage by inducing cellular senescence has not been reported. Here, male C57BL/6 J mice were exposed to benzene vapour for 12 weeks (0, 10, 50 ppm), and mouse hematopoietic progenitor cell line FDC-P1 was exposed to benzene metabolite 1,4-BQ for 24 h (0, 5, 10 μM). In vivo and in vitro models combined with single-cell RNA sequencing have shown that benzene and its metabolites caused senescence in whole bone marrow and hematopoietic progenitor cells. Proteomics showed that benzene exposure significantly up-regulated interferon regulatory factor 4 (Irf4) in the bone marrow. Irf4 inhibition alleviated cellular senescence and hematopoietic damage, suggesting that Irf4 is a key molecule in benzene-induced hematopoietic cell senescence. Mechanistically, benzene caused a decrease in branched-chain amino acids (BCAAs) in whole bone marrow, hematopoietic progenitor cells, and plasma, and an increase in the BCAA catabolic enzyme Bcat1, mitochondrial ROS, and Bckdh activity. Irf4 inhibition down-regulated Bcat1, alleviated mitochondrial oxidative stress-dependent Bckdh abnormality, and up-regulated BCAAs. BCAA supplementation effectively alleviated benzene-induced cellular senescence and hematopoietic damage. In conclusion, the study identified that Irf4 triggered benzene-induced hematopoietic progenitor cell senescence and hematopoietic damage by mitochondrial injury-induced excessive BCAA catabolism. This study provides new ideas on the molecular mechanism of benzene-induced hematopoietic damage from the perspective of metabolism and senescence.