C29-03 Targeting Amphiregulin From Aberrant Transitional Epithelial Stem/Progenitor Cells Blocks Organ Fibrosis

Abstract Rationale Fibrosis is a pathophysiological process originating from defective tissue repair that ultimately leads to organ failure in chronic and progressive diseases. The approved anti-fibrotic agents remain limited in their meaningful treatment effect and tolerability, highlighting the urgent need for novel and safer therapies targeting key upstream mechanisms. The persistence of aberrant transitional epithelial stem/progenitor cells, which adopt a profibrotic state in response to repetitive injury, are now recognized as a central driver of fibrosis. Here, we identified a new target, Amphiregulin (AREG), as a novel molecular driver that links these injury-induced aberrant epithelial stem/progenitor cells with progressive fibrosis. Furthermore, we developed a neutralizing anti-AREG antibody and demonstrated its efficacy in treating organ fibrosis across multiple animal models. Experimental Methods We characterized the expression profiles of AREG in transitional epithelial stem/progenitor cells by single cell RNA-seq and immunofluorescence analyses in mouse and human fibrotic lung, kidney, and liver tissues. To define the function of AREG in organ fibrosis, we conducted comprehensive genetic gain/loss-of-function studies using Areg knockout and Doxycycline-inducible AREG overexpression mice. Finally, we evaluated the anti-fibrotic efficacy of a neutralizing anti-AREG antibody in humanized progressive pulmonary fibrosis and other organ fibrosis models. Results Transcriptome and immunofluorescence analyses revealed that AREG is a top upregulated secreted factor in transitional epithelial stem/progenitor cells across fibrotic lung, kidney, and liver tissues. These cell populations include intermediate alveolar epithelial type 2 cells in the lung, failed-repair proximal tubule epithelial cells in the kidney, and injured hepatocytes in the liver. Functionally, genetic ablation of Areg markedly inhibited fibrosis progression, whereas its ectopic expression was sufficient to induce spontaneous fibrotic lesions in all three organs. These multi-organ data collectively establish sustained AREG expression from injury-induced transitional epithelial stem/progenitor cells as a key molecular driver for organ fibrosis. A therapeutic monoclonal antibody targeting human AREG potently inhibited fibrosis progression, decreased fibrosis-induced body weight loss, and extended survival across multiple preclinical models of organ fibrosis. Conclusions Our findings establish that upregulation of AREG in injury-induced transitional epithelial stem/progenitor cells drives progressive fibrosis, providing a direct mechanistic link between defective tissue repair processes and fibrotic progression. Furthermore, preclinical proof-of-concept studies demonstrate that a neutralizing anti-AREG antibody effectively inhibits fibrosis across diverse organ fibrosis models. Collectively, these results support anti-AREG therapy as a promising and broadly applicable strategy for treating fibrotic disorders. This abstract is funded by: Pulmongene