The respiratory tract is a vital, intricate system for several important biological processes including mucociliary clearance, airway conductance, and gas exchange. The Wnt signaling pathway plays several crucial and indispensable roles across lung biology in multiple contexts. This review highlights the progress made in characterizing the role of Wnt signaling across several disciplines in lung biology, including development, homeostasis, regeneration following injury, in vitro directed differentiation efforts, and disease progression. We further note uncharted directions in the field that may illuminate important biology. The discoveries made collectively advance our understanding of Wnt signaling in lung biology and have the potential to inform therapeutic advancements for lung diseases.

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Highlights d Tracheal epithelial b-catenin tightly controls proliferation and differentiation d PDGFRa + lineage comprises Wnt signaling niche necessary for epithelial proliferation d Airway basal stem cell-derived Wnts facilitate differentiation to ciliated cells d Age-related Wnt/b-catenin niche changes drive gland-like epithelial invaginations

Graphical Abstract Highlights d A dysregulated Wnt/b-catenin axis in human lung premalignancy can be modeled in vitro d High-throughput drug screening identifies the Wnt/b-catenin inhibitor WIC1 d Low-dose treatment with WIC1 promotes differentiation to the ciliated cell fate d WIC1 acts to repress phosphorylation of b-catenin Y489 and Tp63 expression SUMMARYMechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that b-catenin phosphorylated at Y489 (p-b-catenin Y489 ) emerges during human squamous lung cancer progression. This led us to develop a model of airway basal stem cell (ABSC) hyperproliferation by driving Wnt/b-catenin signaling, resulting in a morphology that resembles premalignant lesions and loss of ciliated cell differentiation. To identify small molecules that could reverse this process, we performed a high-throughput drug screen for inhibitors of Wnt/ b-catenin signaling. Our studies unveil Wnt inhibitor compound 1 (WIC1), which suppresses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity, reduces ABSC proliferation, induces ciliated cell differentiation, and decreases nuclear p-b-catenin Y489 . Collectively, our work elucidates a dysregulated Wnt/p-b-catenin Y489 axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/ b-catenin inhibitor that promotes airway homeostasis. WIC1 may therefore serve as a tool compound in regenerative medicine studies with implications for restoring normal airway homeostasis after injury.