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

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. CMA is impaired across fibrotic tissues, driving disease progression. Sunitinib activates CMA by targeting JUND to promote SMAD2/4 degradation, suppressing TGFβ-SMADs-fibrosis signaling. CMA, chaperone-mediated autophagy; IPF, idiopathic pulmonary fibrosis; PF, pulmonary fibrosis; HF, hepatic fibrosis.