Integrated Scaffold Redesign and iPSC-Based Screening Reveal Potent Antifibrotic Artemisinin Analogs in Systemic Sclerosis Models

Abstract

Fibrotic diseases remain among the most intractable human disorders, largely due to the absence of therapies capable of directly modulating the core cellular programs that drive pathological matrix deposition and tissue remodeling. To address this unmet medical need, we report an integrated, chemistry-driven discovery platform for function-oriented molecular design and discovery that combines scaffold redesign of a classical natural product pharmacophore with human induced pluripotent stem cell (iPSC)-based phenotypic screening to identify potent antifibrotic agents. Systematic modification of the artemisinin scaffold led to the identification of 6-aza-artemisinins with markedly enhanced antifibrotic activity, including an N6–N6′ dimeric analog exhibiting high potency at sub-micromolar concentrations. These compounds suppressed collagen production in systemic sclerosis patient-derived fibroblasts and ameliorated fibrosis in a bleomycin-induced murine model, with superior efficacy relative to the clinically used antimalarial drug artesunate. Notably, efficacy was observed even when treatment was initiated after fibrosis establishment. Transcriptomic analysis revealed coordinated suppression of core fibrotic and inflammatory pathways, providing mechanistic insight into the observed therapeutic effects. Collectively, these findings establish 6-aza-artemisinins as a new chemotype for antifibrotic intervention and illustrate how scaffold-level redesign of natural products, integrated with disease-relevant stem-cell-based models, can enable next-generation function-driven therapeutic discovery.