科学者らが新たなシグナル伝達経路を発見し、肝線維症の新規治療薬を設計(Scientists Discover a New Signaling Pathway and Design a Novel Drug for Liver Fibrosis)

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2024-04-25 カリフォルニア大学サンディエゴ校(UCSD)

カリフォルニア大学サンディエゴ校の研究チームは、肝臓の繊維症を防ぐ新たなRNA治療法を開発しました。このRNA、ASO(アンチセンスオリゴヌクレオチド)は、肝臓細胞の特定の転写因子の活性を抑制し、過剰なコラーゲン生成を防ぎます。この発見は、肝線維症の進行において核内スプライシングが重要な役割を果たすことを示しています。また、ASOは特定の疾患に高い効果と特異性を持ち、優れた薬剤設計の例とされています。この研究は、肝硬変や肝臓関連の疾患治療の新たな道を開く可能性があります。

<関連情報>

TM7SF3はTEAD1のスプライシングを制御し、MASH誘発肝線維化を防ぐ TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis

Roi Isaac, Gautam Bandyopadhyay, Theresa V. Rohm, Sion Kang, Jinyue Wang, Narayan Pokhrel, Sadatsugu Sakane, Rizaldy Zapata, Avraham M. Libster, Yaron Vinik, Asres Berhan, Tatiana Kisseleva, Zea Borok, Yehiel Zick, Francesca Telese, Nicholas J.G. Webster, Jerrold M. Olefsky
Cell Metabolism  Published: April 25, 2024
DOI:https://doi.org/10.1016/j.cmet.2024.04.003

Highlights

•TM7SF3 knockdown increases HSC activation and worsens MASH fibrosis in vivo

•Inhibiting TEAD1 splicing with an ASO reduces HSC activation and liver fibrosis

•Active TEAD1ΔEx5 mediates HSC activation and liver fibrosis in MASH

•TM7SF3 inhibits hnRNPU-mediated splicing of TEAD1 into the more active form

Summary

The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis.

Graphical abstract

科学者らが新たなシグナル伝達経路を発見し、肝線維症の新規治療薬を設計(Scientists Discover a New Signaling Pathway and Design a Novel Drug for Liver Fibrosis)

有機化学・薬学
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