Dihydroartemisinin ameliorates radiation lung injury by inhibiting SRC/STAT3 activation and promoting CD204 expression to impede macrophage oxidative stress and M1 polarization.

Radiation lung injury (RLI) involves early macrophage-driven inflammation and oxidative stress, yet effective therapies remain limited. Dihydroartemisinin (DHA) possesses anti-inflammatory and antioxidant properties, but whether it modulates macrophage polarization in RLI is unknown. A mouse model of early RLI was established by thoracic irradiation and treated with DHA. In vitro, a macrophage-epithelial cell co-culture system was used to investigate cell-cell communication. Macrophage polarization was analyzed by flow cytometry, protein expression by Western blot, and oxidative stress markers by ELISA. Direct transcriptional regulation of CD204 by STAT3 was verified using ChIP and dual-luciferase reporter assays in 293 T cells. DHA therapy suppressed M1 polarization, macrophage oxidative stress, and SRC/STAT3 pathway activation in early RLI lungs. Hyperactivation of SRC/STAT3 signaling abolished the therapeutic efficacy of DHA in vitro. Mechanistically, activated STAT3 represses CD204 transcription by binding to the site1 region of its promoter. CD204 overexpression restored the therapeutic effects of DHA, confirming that DHA protects against lung injury by blocking the SRC/STAT3 pathway to enhance CD204 expression, thereby inhibiting oxidative stress, M1 polarization, and epithelial damage. These findings identify the SRC/STAT3/CD204 axis as a critical pathway through which DHA regulates macrophage function in early RLI, providing a mechanistic rationale for repurposing DHA in radiation-induced lung injury.