T‑2 Toxin\nInduces Immunosenescence in RAW264.7\nMacrophages by Activating the HIF-1α/cGAS-STING Pathway

T-2 toxin induces cell immunotoxicity by triggering an\nintracellular\nhypoxic microenvironment and activates hypoxia-inducible factor-1α\n(HIF-1α), which exerts cellular protective effects. Mycotoxins\ncan also induce senescence. The aging of immune function, termed “immunosenescence,”\nis an important factor in the decline of biological immunity and accelerates\nsenescence. However, the mechanism underlying T-2 toxin-induced immunosenescence\nremains unclear. This study aimed to elucidate the roles of HIF-1α\nand cGAS-STING signaling in this process and uncover the mechanisms\nthrough which T-2 toxin impacts cytoskeletal integrity and cellular\nsenescence using a RAW264.7 macrophage model. The cells were treated\nwith T-2 toxin (14 nM) for 1–24 h. We revealed that T-2 toxin-induced\nimmunosenescence in RAW264.7 cells by activating the HIF-1α/cGAS-STING\naxis. The cGAS-STING pathway promotes cell senescence and apoptosis;\nhowever, we revealed that HIF-1α negatively regulated this pathway,\nthereby inhibiting cellular senescence and apoptosis. However, PARP\n1 cleavage by caspase 3/9 inhibited DNA repair and accelerated the\ntransition from senescence to apoptosis. At the late stages of T-2\ntoxin exposure (12 h), HIF-1α accelerated cellular senescence\nby disrupting the dynamic balance of cytoskeletal α-tubulin\nand F-actin and destabilizing the cytoskeletal structure. Our research\ndemonstrates that T-2 toxin induces immunosenescence in RAW264.7 cells\nby activating the cGAS-STING pathway, with HIF-1α signaling\nserving as a negative regulator. This study provides a deeper understanding\nof T-2 toxin-induced immunosenescence.