ATF3 links endoplasmic reticulum stress to ferroptosis via transcriptional activation of ALOX12 in benzene-induced hematotoxicity.

Abstract

As a Class I human carcinogen ubiquitous in both industrial and household environments, benzene can cause hematopoietic damage even at low concentrations. However, its precise hematological toxicological molecular mechanism remains incompletely understood. Here, we demonstrate that hydroquinone (HQ), a benzene metabolite, induces ferroptosis and endoplasmic reticulum stress (ERs) in TK6 cells. Mechanistically, through a combination of RNA-Seq and database analyses, we identified ATF3 as a central molecular switch linking ERs to ferroptosis following HQ treatment, with its activation mediated by the PERK pathway. Using oxidative lipidomics, we further identified ALOX12 as a key lipid peroxidase involved in promoting ferroptosis. Moreover, chromatin immunoprecipitation sequencing (ChIP-Seq) and dual-luciferase reporter assays revealed that ATF3 directly binds to the ALOX12 promoter, triggering its transcriptional activation, which in turn accelerates lipid peroxidation and ultimately leads to ferroptosis. In a mouse model of benzene-induced hematotoxicity, knockdown of ATF3 effectively inhibits bone marrow ferroptosis and markedly ameliorates hematopoietic impairment. Importantly, our cohort study revealed that the higher of ATF3, ALOX12, MDA, and lower GSH/GSSG was significantly associated with hematotoxicity in workers exposed to benzene. Collectively, these findings suggest the ATF3-ALOX12 signal axis may represent promising biomarkers for monitoring early hematopoietic damage resulting from low-dose benzene exposure in environmentally exposed populations.