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<p>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 <i>LAMP2A</i> 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.</p><p></p>

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Deficient chaperone-mediated autophagy drives multiorgan fibrogenesis via SMAD2/4 stabilization to sustain TGFβ-SMAD signaling

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • Jia-yuan Jin,
  • Yu-xuan Song,
  • Jia-bin Lu,
  • Guan-qun Li,
  • Jun-qiang Wang,
  • Xue-jing Feng,
  • Pei-hua Luo,
  • Bo Yang,
  • Zhi-fei Xu,
  • Hao Yan,
  • Qiao-jun He,
  • Xiao-chun Yang

摘要

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.