Phosphorylation of FOXN3 by NEK6 promotes pulmonary fibrosis through Smad signaling

Jinjin Yu, Yingke Li, Yiming Li, Xiaotian Liu, Qingyang Huo, Nan Wu, Yangxia Zhang, Taoling Zeng, Yong Zhang, Henry You Li, Jie Lian, Jihong Zhou, Emmanuel Jairaj Moses (emmanuel_jm@usm.my), Jian Geng (gengjian636@126.com), Juntang Lin (linjtlin@126.com), Wei Li (bbmcliwei@126.com) and Xinxing Zhu (012023112@bbmc.edu.cn)
Additional contact information
Jinjin Yu: Bengbu Medical University
Yingke Li: Xinxiang Medical University
Yiming Li: Bengbu Medical University
Xiaotian Liu: Bengbu Medical University
Qingyang Huo: Xinxiang Medical University
Nan Wu: Bengbu Medical University
Yangxia Zhang: Xinxiang Medical University
Taoling Zeng: Xiamen University
Yong Zhang: Bengbu Medical University
Henry You Li: University of Canterbury
Jie Lian: Xinxiang Medical University
Jihong Zhou: Bengbu Medical University
Emmanuel Jairaj Moses: Universiti Sains Malaysia
Jian Geng: Bengbu Medical University
Juntang Lin: Xinxiang Medical University
Wei Li: Bengbu Medical University
Xinxing Zhu: Bengbu Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The transcriptional repressor FOXN3 plays a key role in regulating pulmonary inflammatory responses, which are crucial in the development of pulmonary fibrosis. However, its specific regulatory function in lung fibrosis remains unclear. Here, we show that FOXN3 suppresses pulmonary fibrosis by inhibiting Smad transcriptional activity. FOXN3 targets a substantial number of Smad response gene promoters, facilitating Smad4 ubiquitination, which disrupts the association of the Smad2/3/4 complex with chromatin and abolishes its transcriptional response. In response to pro-fibrotic stimuli, NEK6 phosphorylates FOXN3 at S412 and S416, leading to its degradation. The loss of FOXN3 inhibits β-TrCP-mediated ubiquitination of Smad4, stabilizing the Smad complex’s association with its responsive elements and promoting transcriptional activation, thus contributing to the development of pulmonary fibrosis. Notably, we found a significant inverse expression pattern between FOXN3 and Smad4 in clinical pulmonary fibrosis cases, underscoring the importance of the NEK6-FOXN3-Smad axis in the pathological process of pulmonary fibrosis.

Date: 2025
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DOI: 10.1038/s41467-025-56922-7

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