Early CYNC-1 Administration Attenuates Radiation-Induced Lung Inflammation and Subsequent Fibrotic Remodeling

Background/Objectives: Radiation-induced lung injury (RILI) involves inflammatory responses followed by fibrotic remodeling. We evaluated CYNC-1, a synthetic compound designed as a lipoxin A4 (LXA4) mimetic, for chemical stability, cellular activity, and attenuation of lung injury after irradiation. Methods: HeLa-derived L132 epithelial-like cells and THP1-Lucia NF-κB reporter monocytes were used for cell-based assays. Male C57BL/6 mice received a single 75-Gy focal lung irradiation. CYNC-1 administration began immediately after irradiation and continued every other day for 2 or 6 weeks. Lung injury was assessed using bronchoalveolar lavage fluid cellularity, micro-computed tomography, histopathology, and lung mechanics. Prednisolone and nintedanib served as reference treatments in the 2- and 6-week cohorts, respectively. Results: CYNC-1 maintained high HPLC area purity during light-protected ethanol storage for 48 h at −78, −20, and 4 °C. It increased survival of irradiated L132 cells and reduced LPS-induced NF-κB reporter activity. In L132 cells, treatment was associated with reduced NF-κB/MAPK and Smad2 phosphorylation and lower profibrotic marker expression. In mice, CYNC-1 reduced inflammatory cell accumulation and collagen deposition and improved lung structure and mechanics. Conclusions: Early and continued CYNC-1 administration attenuated lung inflammation and subsequent fibrotic remodeling in this focal irradiation model. The signaling findings are associative, and FPR2 dependence and efficacy against established fibrosis remain to be established. Validation in primary human lung cells, clinically relevant fractionated irradiation models, animals of both sexes, and tumor models is needed to determine suitability as a normal-tissue protectant, including preservation of antitumor efficacy.