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ResearchIn-Press PreviewCardiologyMetabolism Open Access | 10.1172/JCI182216

Branched chain amino acid transaminase 1-mediated pathway promotes proline-dependent collagen production in cardiac myofibroblasts

Noburo Takizawa,1 Takanori Hironaka,1 Hayato Watanabe,1 Haruna Suetsugu,1 Keisuke Yoshioka,1 Yuma Horii,2 Yuri Nagata,3 Hiroaki Matoba,4 Hidetaka Kosako,5 Kenji Hamase,3 Go Hirai,4 and Michio Nakaya1

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Takizawa, N. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

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1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Watanabe, H. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Suetsugu, H. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Yoshioka, K. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Horii, Y. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Nagata, Y. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Matoba, H. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Kosako, H. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Hamase, K. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Hirai, G. in: PubMed | Google Scholar

1Department of Disease Control, Kyushu University, Fukuoka, Japan

2Department of Pharmacology and Toxicology, Kyushu University, Fukuoka, Japan

3Department of Drug Discovery and Evolution, Kyushu University, Fukuoka, Japan

4Department of Pharmaceutical Synthetic Chemistry, Kyushu University, Fukuoka, Japan

5Division of Cell Signaling, Tokushima University, Tokushima, Japan

Find articles by Nakaya, M. in: PubMed | Google Scholar

Published July 31, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI182216.
Copyright © 2026, Takizawa et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 31, 2026 - Version history
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Abstract

Myofibroblasts are the cells responsible for collagen production, leading to tissue fibrosis. Because 20.5% of the total amino acids in collagen are proline, myofibroblasts must acquire a well-developed proline-producing mechanism during their differentiation. However, the detailed mechanism for myofibroblasts to acquire and keep the developed proline biosynthesis machinery remains obscure. Here, we show branched-chain amino acid transaminase 1 (Bcat1) is up-regulated in a substantial subset of Postn-expressing proto-myofibroblast-like fibroblasts, transitional cells en route to fully differentiated myofibroblasts, as well as in myofibroblasts in the fibrotic heart and liver of mice and humans and promotes the proline production. The branched-chain amino acid (BCAA) production by BCAT1 promotes SMAD3 phosphorylation via HDAC5 phosphorylation at Ser488, thereby enhancing SMAD3-dependent transcription of proline biosynthesis-related genes, Aldh18a1, Pycr1, and Eprs, in proto-myofibroblast-like fibroblasts and myofibroblasts. In BCAT1-deficient mice, expression of proline biosynthesis-related genes is significantly attenuated in their hearts after myocardial infarction, resulting in decreased cardiac fibrosis. Moreover, BCAT1 inhibitor treatment of mice with myocardial infarction reduces cardiac fibrosis. Our results identified a BCAT1-mediated pathway that promotes collagen production via proline biosynthesis regulation in proto-myofibroblast-like fibroblasts and myofibroblasts, which may provide a therapeutic target for cardiac fibrosis.

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Version history
  • Version 1 (July 31, 2026): In-Press Preview
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