Signal transducer and activator of transcription 1–Interferon regulatory factor 1–Acyl-CoA synthetase long-chain family member 4 pathway (STAT1–IRF1–ACSL4 pathway)

The STAT1–IRF1–ACSL4 pathway is a critical signaling axis that mediates the induction of ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation (Wang et al., 2019, Nature; Kong et al., 2023, Redox Biology). Activation of the pathway is typically initiated by interferon-gamma (IFNγ), which triggers the phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1). Phosphorylated STAT1 translocates to the nucleus to induce the expression of Interferon Regulatory Factor 1 (IRF1), which subsequently binds to the promoter of the Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) gene to upregulate its transcription (Kong et al., 2023, Redox Biology). ACSL4 serves as the key executioner by facilitating the esterification of polyunsaturated fatty acids (PUFAs), such as arachidonic acid, into phospholipids, thereby increasing the cell's susceptibility to oxidative damage and ferroptotic death (Jiang et al., 2021, Nat Rev Mol Cell Biol). This pathway is a major mechanism by which CD8+ T cells exert anti-tumor activity during immunotherapy, as they secrete IFNγ to promote ferroptosis in cancer cells (Wang et al., 2019, Nature). Conversely, dysregulation of this axis is implicated in pathological conditions like radiation-induced intestinal injury (RIII), where its inhibition may offer therapeutic protection (Kong et al., 2023, Redox Biology).

Other names

IFNγ–STAT1–IRF1–ACSL4 axisSTAT1/IRF1/ACSL4 signaling pathwayIFN-gamma–STAT1–IRF1–ACSL4 pathwaySTAT1-IRF1-ACSL4 axis

Interferon-gamma (IFNγ) activates the JAK-STAT1 signaling pathway, leading to the phosphorylation and nuclear translocation of STAT1. STAT1 induces the transcription of IRF1, which then binds to the promoter region of the ACSL4 gene to upregulate its expression. ACSL4 catalyzes the esterification of long-chain polyunsaturated fatty acids (PUFAs) into phospholipids, which are the primary substrates for lipid peroxidation, thereby sensitizing the cell to ferroptotic death (Wang et al., 2019; Kong et al., 2023).