STAT1-associated UPR participates in benzene-induced inflammatory-immune imbalance via bone marrow B-cell cycle...

Benzene is a carcinogen lurking in industrial workshops and daily environments. Studies have confirmed that benzene causes persistent inflammation and immunosuppression even at low occupational exposures that meet national standards. However, the key molecules and networks regulating inflammatory-immune disorders have not been elucidated. In this study, occupational benzene-exposed populations had abnormal peripheral blood parameters and systemic inflammatory-immune imbalance, characterized by increased inflammation and immunosuppression. To explore the underlying molecular mechanisms, we constructed a mouse model that approximates occupational exposure conditions and analyzed the single-cell transcriptome data of 22,956 bone marrow (BM) cells. Benzene reduced the proportion of BM B cells, highly consistent with the population's peripheral blood B-lymphocytopenia. Aberrant STAT1 elevation was strongly associated with inflammatory-immune imbalance. Validation in populations and human-derived B cells showed the same trends and correlations. Mechanistically, a STAT1-associated inflammatory factor storm may promote B-cell cycle arrest, potentially through activation of the endoplasmic reticulum unfolded protein response (UPR), thereby contributing to benzene-induced inflammatory-immune imbalance. Thus, the study comprehensively revealed the core role of STAT1 in B cells in benzene-induced hematopoietic damage from population, animal, and cellular perspectives, and elucidated the possibility that Stat1 can trigger cell cycle arrest through the UPR, providing a theoretical basis for intervention.