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ResearchIn-Press PreviewCell biologyMuscle biology Open Access | 10.1172/JCI202212

MESH1-mediated coenzyme A degradation drives ferroptosis sensitivity and muscle pathology

Chao-Chieh Lin,1 Joshua Rose,2 Alexander A. Mestre,1 Chien-Kuang C. Ding,1 Ssu-Yu Chen,1 Sze Mun Choy,3 Kah Yong Goh,3 Weiyi Jiang,3 Wen Xing Lee,3 Qizhou Jiang,3 Yanting Chen,4 Tianai Sun,1 Jianli Wu,1 Yueqi Chen,5 Yunju Oh,5 Pyeonghwa Jeong,5 Jiyong Hong,5 Kenon Chua,6 Michael C. Fitzgerald,5 Guo-Fang Zhang,7 Hong-Wen Tang,8 Pei Zhou,9 and Jen-Tsan Chi10

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Lin, C. in: PubMed | Google Scholar |

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Chen, S. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Jiang, Q. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Wu, J. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Hong, J. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Biochemistry, Duke University School of Medicine, Durham, United States of America

3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

4Department of Anesthesiology, Duke University School of Medicine, Durham, United States of America

5Department of Chemistry, Duke University, Durham, United States of America

6Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore

7Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

8Program in Cancer and Stem Cell Biology, Duke-NUS, Singapore, Singapore

9Department of Biochemistry, Duke University, Durham, United States of America

10Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Chi, J. in: PubMed | Google Scholar |

Published April 25, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI202212.
Copyright © 2026, Lin 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 April 25, 2026 - Version history
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Abstract

Coenzyme A (CoA) facilitates fatty acid synthesis, energy production, gene regulation, and antioxidant function. While CoA biosynthesis is well-characterized, the mechanisms governing CoA degradation remain poorly understood. Here, we identify the Metazoan Homolog of SpoT, MESH1, as a CoA phosphatase that dephosphorylates CoA at the 3’ position of the ribose ring to form dephospho-CoA (dp-CoA). Recent studies have shown that CoA, similar to glutathione (GSH), is a cysteine-derived metabolite that protects cells against ferroptosis. Ferroptosis induced by blocking cystine import depletes CoA biosynthesis, while CoA restoration rescues cells from ferroptosis. We found that MESH1 knockdown preserved CoA levels by preventing its degradation, contributing to ferroptosis protection, indicating the bifunctional role of MESH1 in regulating CoA and previously reported NADPH. Mechanistically, MESH1 knockdown elevates CoA levels, maintaining functional mitochondrial thioredoxin system, thereby preventing mitochondrial lipid peroxidation. In Drosophila, we found that dMesh1 overexpression leads to ferroptosis-mediated muscle atrophy, which can be rescued by increasing CoA and NADPH levels. Taken together, these findings establish MESH1 as a key phosphatase that governs ferroptosis sensitivity by coordinating CoA and NADPH homeostasis, unveiling a novel link between CoA degradation, mitochondrial integrity, and muscle health.

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