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. 2024 Mar 3;20(5):1871–1883. doi: 10.7150/ijbs.91112

Figure 4.

Figure 4

Regulative mechanism of inhibitors for treating ferroptosis-related radiation damage. Radiotherapy can stimulate (A) iron metabolism and (B) ROS metabolism while inhibiting (C) the system Xc--GPX4 axis, ultimately inducing ferroptosis. This process is suppressed by several inhibitors. (A) Iron metabolism: NCOA4 promotes ferritinophagy, inhibiting the expression of iron storage-related proteins such as FTH and FTL, while suppressing FPN1 and enhancing TRF1, thereby synergistically promoting iron metabolism. Activation of HO-1, facilitated by NRF2, further inhibits iron metabolism. Dysregulated iron metabolism leads to ROS accumulation. (B) ROS metabolism: NRF2 upregulates NQO1, which counteracts ROS levels elevated by ACSL4 and induces increased PTGS2 expression. Elevated ROS levels promote lipid peroxidation, triggering ferroptosis. (C) System Xc--GPX4: SLC38A9 activates mTOR, inhibiting system Xc- comprised of SLC7A11 and SLC3A2. Cystine influx via system Xc- activates the GSH/GPX4 axis, inhibiting ROS accumulation. ACSL4 indirectly inhibits system Xc- and GPX4, thereby promoting ROS accumulation. Ferroptosis induction leads to the release of cytokines, including IL-1β, IL-6, IL-10, TNF-α, and TGF-β1.