PRMT5 lactylation mediates SIRT6-dependent DNA damage and senescence in benzene-induced hematotoxicity

Benzene exposure induces hematotoxicity, partially through disrupted DNA damage repair. SIRT6 is a key regulator of both DNA repair and metabolism. While its connection to metabolic reprogramming and novel lactylation modifications in benzene toxicity remains unknown. Herein, we found decreased SIRT6 expression in the peripheral WBCs of benzene-exposed workers. Furthermore, mediation analysis identified SIRT6, p16, and serum γ-H2AX levels as mediators of the inverse relationship between urinary S-PMA and WBC counts. In vitro, benzoquinone (BQ) suppressed SIRT6, enhanced glycolysis and lactate production, and induced DNA double-strand breaks (DSBs) and senescence. SIRT6-knockdown models confirmed that SIRT6 deficiency exacerbates benzene-induced increase in glycolysis and lactate accumulation. Crucially, lactate reduction with DCA attenuated DSBs and cellular senescence in bone marrow cells, mitigating hematopoietic damage. Mechanistically, we identified PRMT5 as a novel lactylation target of SIRT6 at lysine 240 (K240), a process that SIRT6 regulated through the lactyltransferase TIP60 and delactylase HDAC1. Functional studies in K240-mutant cells demonstrated that blocking lactylation at this site alleviated BQ-induced DSBs and senescence. Our findings establish that SIRT6 deficiency drives a lactate-fuelled lactylation of PRMT5 at K240, impairing DNA repair and promoting hematopoietic stem cell senescence caused by benzene. This work elucidates a previously unrecognized metabolic-epigenetic axis in benzene toxicity and highlights the therapeutic potential of targeting glycolytic flux or specific lactylation events to combat chemical-induced hematological damage.