Abstract Rationale The persistent activation of lung fibroblasts (LFB) into myofibroblasts drives Progressive Pulmonary Fibrosis (PPF), a shared phenotype of progressive fibrosis across various Interstitial Lung Diseases (ILDs), for which effective therapeutic options remain limited. Aza-Artemisinin (Aza-A) derivatives have shown anti-fibrotic properties in other organs, e.g., inhibiting hepatic stellate cell activation in liver cirrhosis and attenuating post-myocardial infarction cardiac fibrosis, but their efficacy in human LFB, particularly those derived from diseased ILD lungs, remains unexplored. We hypothesized that two novel Aza-A derivatives, TKN9 and TKN11, inhibit TGF-β1-induced myofibroblast differentiation in primary human LFB. Methods Primary LFB lines were established from non-fibrotic lung tissue (Normal-LFB) and explanted end-stage ILD lungs (end-ILD-LFB). Cells were serum-starved and stimulated with TGF-β1 to induce a pro-fibrotic state, then the cells were treated with TKN9 or TKN11. The anti-fibrotic effect was quantified by assessing the gene and protein expression of key myofibroblast and extracellular matrix markers: α-smooth muscle actin (ACTA2) and Collagen Type I (COL1A1). Results TGF-β1 stimulation robustly induced the expression of ACTA2 and COL1A1 in LFB. Treatment with both TKN9 and TKN11 significantly and concentration-dependently suppressed the TGF-β1-induced expression of both ACTA2 and COL1A1. Importantly, this potent anti-fibrotic effect was observed in both Normal-LFB and end-ILD-LFB, demonstrating efficacy in disease-relevant cells. Conclusion Novel Aza-Artemisinin derivatives TKN9 and TKN11 effectively inhibit the TGF-β1-driven differentiation of human lung fibroblasts into pathogenic myofibroblasts. The ability to suppress the fibrotic phenotype, even in cells derived from end-stage ILD patients, establishes Aza-A derivatives as a promising new therapeutic reagent for ILD. This abstract is funded by: None
Suzue et al. (Fri,) studied this question.