Cryptotanshinone is a candidate therapeutic agent for interstitial lung disease associated with a BRICHOS-domain mutation of SFTPC

• Published in: iScience Vol. 26; no. 10; p. 107731
• Main Authors: Hosokawa, Motoyasu, Mikawa, Ryuta, Hagiwara, Atsuko, Okuno, Yukiko, Awaya, Tomonari, Yamamoto, Yuki, Takahashi, Senye, Yamaki, Haruka, Osawa, Mitsujiro, Setoguchi, Yasuhiro, Saito, Megumu K., Abe, Shinji, Hirai, Toyohiro, Gotoh, Shimpei, Hagiwara, Masatoshi
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 20.10.2023; Elsevier
• Subjects: Biochemistry; Cell biology; Molecular biology; Stem cells research; Cell biology; Biochemistry; Stem cells research; Molecular biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.107731

Interstitial lung disease (ILD) represents a large group of diseases characterized by chronic inflammation and fibrosis of the lungs, for which therapeutic options are limited. Among several causative genes of familial ILD with autosomal dominant inheritance, the mutations in the BRICHOS domain of SFTPC cause protein accumulation and endoplasmic reticulum stress by misfolding its proprotein. Through a screening system using these two phenotypes in HEK293 cells and evaluation using alveolar epithelial type 2 (AT2) cells differentiated from patient-derived induced pluripotent stem cells (iPSCs), we identified Cryptotanshinone (CPT) as a potential therapeutic agent for ILD. CPT decreased cell death induced by mutant SFTPC overexpression in A549 and HEK293 cells and ameliorated the bleomycin-induced contraction of the matrix in fibroblast-dependent alveolar organoids derived from iPSCs with SFTPC mutation. CPT and this screening strategy can apply to abnormal protein-folding-associated ILD and other protein-misfolding diseases. [Display omitted] •A phenotypic screening system targeting SFTPC mutation was established•ILD patient-derived iPSC were applied to evaluating candidate chemical compounds•Cryptotanshinone suppressed cell death caused by SFTPC mutation•Cryptotanshinone ameliorated the fibrosis phenotype of the patient-derived iPSC Biochemistry; Molecular biology; Cell biology; Stem cells research