Xinxing Zhu, Qingyang Huo, Lele Jin, Jiang Du, Jinjin Yu, Huanhuan Wang, Nan Wu, Yingke Li, Rui Yan, chengling Zhao, Jihong Zhou, Yong Zhang, Han Li, Juntang Lin, Chunfu Zheng, Wei Li
The transcriptional repressor forkhead box N3 (FOXN3) has been reported to suppress pulmonary fibrosis by inhibiting Smad transcriptional activity. However, FOXN3 becomes unstable in response to profibrotic stimuli. This study identifies poly(ADP-ribose) polymerase-1 (PARP1) as a stabilizing partner of FOXN3, preventing its degradation by blocking p38-mediated phosphorylation. Lung-specific knockout (KO) of PARP1 promotes the development of pulmonary fibrosis by reducing the abundance of FOXN3. Conditional overexpression of FOXN3 notably mitigates pulmonary fibrosis resulting from PARP1 KO by impeding Smad signaling, underscoring the critical role of the PARP1-FOXN3 axis in pulmonary fibrosis. Mechanistically, p38 is a Smad response gene that is transcriptionally repressed by the PARP1/FOXN3 complex. The disruption of PARP1 or FOXN3 increases p38 expression, which in turn facilitates FOXN3 degradation through a feedback mechanism. This cascade activates Smad signaling, leading to a profibrotic response and myofibroblast activation. Notably, levels of PARP1 and FOXN3 are significantly reduced in patients with pulmonary fibrosis, highlighting PARP1's crucial role in suppressing the disease by regulating FOXN3-mediated Smad signaling.