2. Academic Validation
  3. Extracellular HSP90α promotes cellular senescence by modulating TGF-β signaling in pulmonary fibrosis

Extracellular HSP90α promotes cellular senescence by modulating TGF-β signaling in pulmonary fibrosis

  • FASEB J. 2022 Aug;36(8):e22475. doi: 10.1096/fj.202200406RR.
Wenshan Zhong 1,  Weimou Chen 1,  Yuanyuan Liu 1,  Jinming Zhang 1,  Ye Lu 1,  Xuan Wan 1,  Yujie Qiao 1,  Haohua Huang 1,  Zhaojin Zeng 1,  Wei Li 2,  Xiaojing Meng 3,  Haijin Zhao 1,  Mengchen Zou 4,  Shaoxi Cai 1,  Hangming Dong 1
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2 Department of Dermatology, The USC-Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, California, USA.
  • 3 Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Occupational Health and Occupational Medicine, School of Public Health, Southern Medical University, Guangzhou, China.
  • 4 Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China.
PMID: 35899478 DOI: 10.1096/fj.202200406RR
Abstract

Recent findings suggest that extracellular heat shock protein 90α (eHSP90α) promotes pulmonary fibrosis, but the underlying mechanisms are not well understood. Aging, especially cellular senescence, is a critical risk factor for idiopathic pulmonary fibrosis (IPF). Here, we aim to investigate the role of eHSP90α on cellular senescence in IPF. Our results found that eHSP90α was upregulated in bleomycin (BLM)-induced mice, which correlated with the expression of senescence markers. This increase in eHSP90α mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90α activated TGF-β signaling through the phosphorylation of the SMAD complex. The SMAD complex binding to p53 and p21 promoters triggered their transcription. In vivo, the blockade of eHSP90α with 1G6-D7, a specific eHSP90α antibody, in old mice attenuated the BLM-induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90α-induced cellular senescence, providing a framework for aging-related fibrosis interventions.

Keywords

HSP90 heat-shock proteins; cellular senescence; mitochondria; pulmonary fibrosis; reactive oxygen species; transforming growth factor beta.

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