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ResearchIn-Press PreviewAgingHepatologyMetabolism Open Access | 10.1172/jci.insight.207066

Hepatocyte hedgehog signaling controls ferroptosis to alleviate aging-related organ dysfunction

Ji Hye Jun,1 Rajesh K. Dutta,1 Soon-Woo Cho,2 Rui Yao,2 Seh Hoon Oh,1 Zhi Li,3 Kuo Du,1 David S. Umbaugh,1 Nanchao Wang,2 Yirui Xu,2 Jingting Li,2 Lingyan Shi,3 Jen-Tsan Chi,4 Junjie Yao,2 and Anna Mae Diehl1

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Yao, R. in: PubMed | Google Scholar

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Li, Z. in: PubMed | Google Scholar

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Umbaugh, D. in: PubMed | Google Scholar

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Shi, L. in: PubMed | Google Scholar

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

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

1Division of Gastroenterology, Duke University, Durham, United States of America

2Department of Biomedical Engineering, Duke University, Durham, United States of America

3Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, San Diego, United States of America

4Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

Find articles by Diehl, A. in: PubMed | Google Scholar

Published May 19, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.207066.
Copyright © 2026, Jun 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 May 19, 2026 - Version history
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Abstract

Aging drives systemic metabolic dysfunction (SMD) and increases the risk of chronic illnesses such as metabolic dysfunction–associated steatotic liver disease (MASLD) and chronic kidney disease (CKD). However, mechanisms that connect aging to multi-organ deterioration are poorly understood. In this study, we identify hepatocyte Hedgehog signaling as a central regulator of ferroptosis. Using mice with hepatocyte-specific deletion of Smoothened (Smo), a key Hedgehog pathway component, we show that loss of hepatocyte Hedgehog signaling induces ferroptotic stress, lipid peroxidation, and cellular senescence. These changes were sufficient to cause spontaneous MASLD and to trigger secondary kidney injury. Smo deletion also disrupted systemic iron balance, increased hepatocyte production of the angiotensinogen, and reduced liver perfusion. Similar responses (iron dysregulation, vascular dysfunction, and reduced Hedgehog signaling) were observed in patients with MASLD and advanced fibrosis. Inhibition of ferroptosis with ferrostatin-1 reversed hepatocyte senescence, restored hepatic blood flow, and improved both liver and kidney injury in Smo-deficient mice. Overall, these findings show that hepatocyte Hedgehog signaling preserves liver homeostasis by restraining ferroptotic stress and coordinating iron-dependent vasoactive pathways. The results reveal an unrecognized aging-related communication axis between liver and kidney and identify the Hedgehog–ferroptosis pathway as a promising therapeutic target for age-associated metabolic diseases.

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  • Version 1 (May 19, 2026): In-Press Preview
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