The rising prevalence of acetyl tributyl citrate (ATBC) as an environmental pollutant has raised significant concerns regarding its immunomodulatory effects, necessitating this investigation into its potential immunotoxicity and underlying molecular mechanisms in systemic lupus erythematosus (SLE) through an integrated approach of network toxicology, molecular docking, and in vitro validation using primary PBMCs from SLE patients and healthy controls. Following the identification of 139 intersection targets and the confirmation of stable binding affinities between ATBC and core hubs such as STAT3, BCL2, and GSK3β, our experimental data revealed a distinct differential susceptibility, where SLE-derived PBMCs exhibited a significantly lower toxic threshold (IC50 = 49.8 μM) compared to NC PBMCs (IC50 = 68.7 μM) at 36 h. ATBC exposure significantly exacerbated oxidative stress and triggered a pro-inflammatory "cytokine storm"-characterized by elevated IFN-γ, TNF-α, IL-2, and IL-6 alongside diminished IL-10-with these effects being markedly more pronounced in the SLE group. Mechanistically, ATBC-induced ROS accumulation led to the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and a coordinated downregulation of the exonuclease TREX1, a dual impairment of DNA clearance that triggered the cGAS-STING sensing pathway as evidenced by the robust upregulation of cGAS, STING, and phosphorylated STING (p-STING). Furthermore, RT-qPCR and Western blot analysis confirmed the dysregulation of downstream survival and inflammatory markers, including BCL2, GSK3β, STAT3, and EGFR. Collectively, these findings systematically demonstrate that ATBC acts as a potent environmental trigger that lowers the threshold for innate immune activation in SLE by disrupting redox homeostasis and activating the DNA-sensing axis, providing a robust theoretical and experimental basis for the toxicological risk assessment of "safe" plasticizer alternatives in autoimmune diseases.
Li et al. (Sat,) studied this question.