Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease that primarily affects older adults. Current FDA-approved therapies slow functional decline but do not halt disease progression or reverse established fibrosis. We and others have shown that deficient activation of the antioxidant transcription factor Nrf2 contributes to persistent, age-associated fibrosis. Dimethyl fumarate (DMF) and monomethyl fumarate (MMF) are FDA-approved oral Nrf2 activators for multiple sclerosis and represent attractive candidates for therapeutic repurposing in IPF. We previously demonstrated that Nrf2 activation reverses established lung fibrosis in aged murine models (Kato et. al., Antioxidant, 2025). Here, we assessed the antifibrotic efficacy of DMF and MMF in human IPF fibroblasts and ex vivo precision-cut lung slices (PCLS) to evaluate translational potential. Methods Primary human IPF lung fibroblasts were treated with DMF or MMF (100 µM, 24 h), followed by assessment of Nrf2 protein expression (Western blot) and profibrotic gene expression (qPCR). Parallel studies were performed in human IPF PCLS derived from five independent IPF donors (n = 5) and treated with DMF or MMF (100 µM, 72 h). Tissue viability was assessed by WST-1, and fibrosis-associated transcripts were quantified from bulk RNA. Results In PCLS (n = 5 donors) treated at 100μM, neither DMF nor MMF showed cytotoxicity by WST-1 assay, confirming assay viability. Both compounds induced Nrf2 pathway activation in IPF fibroblasts and significantly reduced expression of profibrotic ECM genes, including COL1A1. In PCLS, both compounds similarly suppressed collagen transcripts and additional matrix-remodeling markers, supporting conserved antifibrotic activity in a multicellular human lung environment. These data are consistent with prior in vivo findings that Nrf2 activation reduces established lung fibrosis in aged mice. Conclusions Our results provide proof-of-concept that repurposed Nrf2 activators exert antifibrotic effects in human IPF cells and PCLS. Given their FDA approval and safety profile, these Nrf2 activators represent a novel drug-repurposing approach for targeting oxidative stress to reduce age-dependent established fibrosis. These data support continued development of lung-targeted Nrf2 activators as a therapeutic approach for IPF, with next steps including optimized pulmonary delivery and in-human feasibility studies. This abstract is funded by: NIH
Kato et al. (Fri,) studied this question.