SENP1-Sirt3 axis regulates type II alveolar epithelial cell activity to confer resistance against oxidative damage in lung tissue

SENP1-Sirt3 axis regulates type II alveolar epithelial cell activity to confer resistance against oxidative damage in lung tissue

Oxidative damage exacerbates pulmonary fibrosis by impairing alveolar type II epithelial (AT2) cell function. This study demonstrates that the SUMO-specific protease 1 (SENP1)-Sirtuin 3 (Sirt3) axis, critical for mitochondrial redox regulation, is suppressed in AT2 cells during lung injury. In bleom...

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Bibliographic Details
Main Authors: Mingming Zhang, Xin Lin, Jianli He, Yong Zuo, Qiuju Fan, Innocent Agida, Hongsheng Tan, Caiying Zhu, Jinke Cheng, Tianshi Wang
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Redox Biology
Subjects:
SENP1-Sirt3 axis
AT2 cell
Oxidative damage
Mitochondria
Lung fibrosis
Online Access:http://www.sciencedirect.com/science/article/pii/S2213231725002654
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Summary:Oxidative damage exacerbates pulmonary fibrosis by impairing alveolar type II epithelial (AT2) cell function. This study demonstrates that the SUMO-specific protease 1 (SENP1)-Sirtuin 3 (Sirt3) axis, critical for mitochondrial redox regulation, is suppressed in AT2 cells during lung injury. In bleomycin-induced pulmonary fibrosis models, activating the SENP1-Sirt3 axis via Sirt3 SUMOylation site mutation (Sirt3 K223R) reduced Superoxide Dismutase 2 (SOD2) acetylation, thereby lowering mitochondrial reactive oxygen species (mtROS) accumulation and apoptosis. This intervention increased AT2 cell proliferation and differentiation into alveolar type I cells while reducing Keratin 8 (KRT8)+ transitional cell number, a profibrotic population. Additionally, SENP1-Sirt3 activation attenuated inflammation and fibrosis in lung tissue. Transcriptomic analysis linked the axis to enhanced Wnt signaling and lipid metabolism pathways, promoting AT2 stemness. Antioxidant N-acetylcysteine (NAC) supplementation mirrored these benefits, reinforcing ROS clearance as a therapeutic mechanism. These findings highlight SENP1-Sirt3 as a pivotal regulator of AT2 resilience, offering a potential strategy to mitigate fibrosis by targeting mitochondrial oxidative stress and cellular plasticity.
ISSN:2213-2317

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