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

Motoyasu Hosokawa; Ryuta Mikawa; Atsuko Hagiwara; Yukiko Okuno; Tomonari Awaya; Yuki Yamamoto; Senye Takahashi; Haruka Yamaki; Mitsujiro Osawa; Yasuhiro Setoguchi; Megumu K Saito; Shinji Abe; Toyohiro Hirai; Shimpei Gotoh; Masatoshi Hagiwara

doi:10.1016/j.isci.2023.107731

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

iScience. 2023 Aug 25;26(10):107731. doi: 10.1016/j.isci.2023.107731. eCollection 2023 Oct 20.

Authors

Motoyasu Hosokawa^{1

2}, Ryuta Mikawa^{3

4

5}, Atsuko Hagiwara^{1

3}, Yukiko Okuno⁶, Tomonari Awaya¹, Yuki Yamamoto^{3

4}, Senye Takahashi^{4

5}, Haruka Yamaki^{3

5}, Mitsujiro Osawa⁵, Yasuhiro Setoguchi⁷, Megumu K Saito⁵, Shinji Abe⁸, Toyohiro Hirai³, Shimpei Gotoh^{3

4

5}, Masatoshi Hagiwara¹

Affiliations

¹ Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
² Department of Developmental Biology and Functional Genomics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.
³ Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
⁴ Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁵ Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
⁶ Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
⁷ Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, Japan.
⁸ Department of Respiratory Medicine Tokyo, Medical University Hospital, Shinjuku-ku, Tokyo 160-0023, Japan.

Abstract

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.

Keywords: Biochemistry; Cell biology; Molecular biology; Stem cells research.