ABRL8301, a Novel 2-Methoxyestradiol Derivative, Mitigates Progressive Pulmonary Fibrosis by Downregulating 11β-Hydroxysteroid Dehydrogenase 1.

Progressive pulmonary fibrosis (PPF) is a severe lung disease characterized by persistent tissue damage and scarring, with no curative therapies currently available. The multifactorial and poorly understood pathogenesis complicates drug development, highlighting the need for novel multi-targeted anti-fibrotic therapeutics. Our previous study established a phenotypic screening platform identifying inhibitors of radiation-induced endothelial-to-mesenchymal transition. The screening revealed that 2-methoxyestradiol (2-ME), a hypoxia-inducible factor (HIF)-1α inhibitor, altered morphology and ultrastructure with abrogation of actin stress fibers in radiation-treated human umbilical vein endothelial cells (HUVECs). In this study, we synthesized 15 novel 2-ME derivatives to enhance anti-fibrotic efficacy. Among them, ABRL8301 showed the greatest potency, promoting mesenchymal-to-endothelial transition (MEndT) and reducing mesenchymal markers. ABRL8301 reduced 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression and concomitantly increased heme oxygenase-1 (HO-1) levels in fibrosis-relevant cell types, which we interpret as pathway-level evidence consistent with 11β-HSD1 engagement rather than direct pharmacodynamic target validation. This leads to decreased NF-κB nuclear translocation, HIF-1α, and extracellular matrix protein levels, enhancing MEndT/mesenchymal-to-epithelial transition (MET) and suppressing fibrotic progression. In macrophages, ABRL8301 inhibits NF-κB signaling, promotes polarization toward the M2 anti-inflammatory phenotype, and suppresses interleukin-6 expression, contributing to its anti-fibrotic and immunomodulatory effects. Furthermore, ABRL8301 significantly attenuated PPF in both bleomycin- and radiation-induced mouse models, showing more pronounced histological and radiological improvement in lung consolidation and collagen deposition compared with nintedanib at the tested doses. ABRL8301 also mitigated radiation-induced skin vascular injury and collagen accumulation. Collectively, these findings identify ABRL8301 as a promising therapeutic candidate for PPF via the 11β-HSD1/HO-1/HIF-1α axis.