2. Academic Validation
  3. Phosphorylation of FOXN3 by NEK6 promotes pulmonary fibrosis through Smad signaling

Phosphorylation of FOXN3 by NEK6 promotes pulmonary fibrosis through Smad signaling

  • Nat Commun. 2025 Feb 21;16(1):1865. doi: 10.1038/s41467-025-56922-7.
Jinjin Yu # 1 2 3,  Yingke Li # 4,  Yiming Li # 5,  Xiaotian Liu # 5,  Qingyang Huo # 4,  Nan Wu 3,  Yangxia Zhang 4,  Taoling Zeng 6,  Yong Zhang 1,  Henry You Li 7,  Jie Lian 4,  Jihong Zhou 5,  Emmanuel Jairaj Moses 8,  Jian Geng 9,  Juntang Lin 10,  Wei Li 11,  Xinxing Zhu 12
Affiliations

Affiliations

  • 1 Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease, Department of Respiratory and Critical Care Medicine, First Affiliated Hospital, Bengbu Medical University, Bengbu, China.
  • 2 Regenerative Medicine Sciences Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Malaysia.
  • 3 Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University, Bengbu, China.
  • 4 Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, China.
  • 5 Research Center of Clinical Laboratory Science, School of Laboratory Medicine, Bengbu Medical University, Bengbu, China.
  • 6 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Fujian, China.
  • 7 Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand.
  • 8 Regenerative Medicine Sciences Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Malaysia. emmanuel_jm@usm.my.
  • 9 Research Center of Clinical Laboratory Science, School of Laboratory Medicine, Bengbu Medical University, Bengbu, China. gengjian636@126.com.
  • 10 Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, China. linjtlin@126.com.
  • 11 Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease, Department of Respiratory and Critical Care Medicine, First Affiliated Hospital, Bengbu Medical University, Bengbu, China. bbmcliwei@126.com.
  • 12 Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease, Department of Respiratory and Critical Care Medicine, First Affiliated Hospital, Bengbu Medical University, Bengbu, China. 012023112@bbmc.edu.cn.
  • # Contributed equally.
PMID: 39984467 DOI: 10.1038/s41467-025-56922-7
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.

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