Role of Klhl14 in senescence and epithelial-to-mesenchymal transition via TGF-β modulation.

KLHL14, a component of an E3-ubiquitin ligase complex, has emerged as a context-dependent oncogene or tumor suppressor, particularly important for thyroid development. Yet its role in thyroid biology remains largely unexplored. In this study, we uncover a central function for KLHL14 in maintaining thyroid epithelial identity and regulating tissue homeostasis. Using a thyroid organoid model, we show that KLHL14 is essential for the proper growth and maturation of thyroid cells. Reduction of KLHL14 expression disrupts organoid development and triggers a dual cellular response involving features of both senescence and an epithelial-to-mesenchymal-like transition. These phenotypic changes are accompanied by increased cellular plasticity, loss of epithelial identity, and migratory capacity. Mechanistically, we identify TGF-β signaling as a key pathway activated upon KLHL14 depletion, contributing to the observed cellular reprogramming. Inhibiting TGF-β restores growth and reduces EMT-associated and senescence markers, positioning KLHL14 as an upstream modulator of this signaling axis. These findings reveal a previously unrecognized role for KLHL14, suggesting that its homeostasis is pivotal to thyrocyte fitness and epithelial identity. This work broadens our understanding of thyroid epithelial biology and reveals molecular insights applicable to other tissues, thereby defining the multifaceted role of this E3 Ubiquitin ligase within its intricate network.