@article{APS11612,
author = {Jia-yuan Jin and Yu-xuan Song and Jia-bin Lu and Guan-qun Li and Jun-qiang Wang and Xue-jing Feng and Pei-hua Luo and Bo Yang and Zhi-fei Xu and Hao Yan and Qiao-jun He and Xiao-chun Yang},
title = {Deficient chaperone-mediated autophagy drives multiorgan fibrogenesis via SMAD2/4 stabilization to sustain TGFβ-SMAD signaling},
journal = {Acta Pharmacologica Sinica},
volume = {47},
number = {9},
year = {2026},
keywords = {},
abstract = {Fibrotic diseases, driven by excessive extracellular matrix deposition, account for substantial global morbidity and mortality, yet effective therapies remain elusive. Emerging evidence highlights impaired protein homeostasis as a key contributor to fibrosis, prompting exploration of autophagy-mediated degradation pathways. Here, we investigate the role of chaperone-mediated autophagy (CMA), a selective lysosomal degradation mechanism, in fibrosis progression. We demonstrate that CMA activity is suppressed in fibrotic tissues from experimental mice and human patients, correlating with pathological SMAD2/4 accumulation. Mechanistically, CMA deficiency impedes SMAD2/4 degradation, amplifying TGF-β signaling and collagen overproduction. AAV- mediated LAMP2A overexpression to restore CMA activity alleviated bleomycin-induced pulmonary fibrosis and carbon tetrachloride-induced hepatic fibrosis in mice. Furthermore, we identify sunitinib, an FDA-approved tyrosine kinase inhibitor, as a novel CMA activator that enhances LAMP2A transcription via targeting the transcription factor JUND, reduces SMAD2/4 levels, and mitigates fibrosis in vivo. Our findings establish CMA dysfunction as a common pathological hallmark of fibrotic diseases and unveil therapeutic strategies targeting CMA to restore protein homeostasis. This study provides critical insights into fibrosis pathogenesis and positions pharmacological CMA activation as a promising treatment avenue.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11612}
}