Golidocitinib ameliorates radio-immunotherapy-induced lung injury by alleviating oxidative stress and Pyroptosis.
Abstract
Background
The combination of radiotherapy and immunotherapy (iRT) is effective against lung cancer but increases the risk of pulmonary toxicity. This iRT-induced lung injury (iRT-LI) may lead to treatment interruption and consequently worsen clinical outcomes. Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, exhibits anti-inflammatory and immunomodulatory properties. This study aimed to explore its therapeutic effect and underlying mechanism against iRT-LI, thereby addressing key scientific questions regarding pulmonary toxicity.
Methods
Olink proteomic analysis of clinical patient blood samples identified key signaling pathways. A mouse model of iRT-LI was established using a single dose of 20 Gy thoracic radiation combined with 200 μg of αPD-1 administered twice weekly for three weeks. The roles of inflammation and fibrosis were evaluated through histology and cytokine array detection. Flow cytometry, immunofluorescence, and western blotting were employed to systematically assess cell polarization, mitochondrial function, oxidative stress, and pyroptosis.
Results
Aberrant activation of the JAK-STAT pathway may represent a key mechanism underlying iRT-LI. Golidocitinib conferred significant protection through its dual anti-inflammatory and anti-fibrotic effects. Specifically, the protective effects of Golidocitinib were associated with reduced cytokine levels, leading to decreased macrophage-dominant immune infiltration and suppression of early M1 polarization. Golidocitinib improved macrophage mitochondrial dysfunction and inhibited the oxidative stress response induced by iRT. Moreover, it specifically targeted the downstream STAT3 signaling pathway, decreasing NLRP3 transcription and thereby mitigating iRT-induced pyroptosis and inflammation.
Conclusion
Golidocitinib alleviated iRT-LI by reducing macrophage infiltration and inhibiting M1 polarization, oxidative stress, and pyroptosis. These findings provide new insights into the mechanisms underlying iRT-related pulmonary toxicity.