Tankyrase inhibition demonstrates anti-fibrotic effects in preclinical pulmonary fibrosis models
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. Although transforming growth factor beta 1 (TGFB1, TGFβ) is a key driver of fibrosis, additional signaling pathways, including wingless-type mammary tumor virus integration site (WNT)/β-catenin and yes-associated protein 1 (YAP), contribute to IPF pathogenesis. Clinical data indicate that inhibition of TGFβ alone provides limited efficacy or is associated with toxicity, underscoring the need for alternative therapeutic approaches. Tankyrase (TNKS) 1 and 2 are post-translational regulators of WNT/β-catenin and YAP signaling and therefore represent promising antifibrotic targets. OM-153, a potent and selective TNKS inhibitor, exhibits pharmacological properties suitable for preclinical development in IPF.
Methods
Primary normal human lung fibroblasts (NHLF), Scar-in-a-Jar assays, lung-on-a-chip models, and precision-cut lung slices (PCLS) from non-pulmonary fibrosis (non-PF) tissue were stimulated with an IPF-relevant cytokine cocktail (IPF-RC) designed to accurately recapitulate the pro-fibrotic environment and compared to TGFβ. These models, with bleomycin-challenged mice and PCLS from end-stage pulmonary fibrosis (PF) patients, were treated with OM-153. Fibrosis markers, extracellular matrix (ECM) components, and signaling pathway-specific gene expression or protein markers were assessed by real-time qRT-PCR, RNA sequencing, immunoblotting, ELISA, and immunofluorescence.
Results
OM-153 stabilized the direct TNKS targets axin 1 (AXIN1) and angiomotin-like 1 (AMOTL1), suppressed WNT/β-catenin and YAP signaling. In parallel, it reduced profibrotic ECM expression across in vitro , in vivo , and ex vivo IPF models.
Conclusions
Selective TNKS inhibition by OM-153 demonstrates broad antifibrotic activity in multiple preclinical models, supporting further development as a potential disease-modifying strategy for IPF.
Shareable abstract
Our findings show that the potent and selective TNKS inhibitor OM-153 suppresses WNT/β-catenin and YAP signaling, reducing pro-fibrotic ECM expression in preclinical IPF models, supporting TNKS inhibition as a novel antifibrotic strategy.
