Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease
Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.
Authors
- Stavros Drakos (ORCID: https://orcid.org/0000-0002-8626-7931)
- Enrique Balderas (ORCID: https://orcid.org/0000-0001-8780-9272)
- Dipayan Chaudhuri (ORCID: https://orcid.org/0000-0003-0605-7334)
- Scott A. Summers (ORCID: https://orcid.org/0000-0002-4919-0592)
- Robin M. Shaw (ORCID: https://orcid.org/0000-0001-7429-6092)
- Anthony M. Balynas (ORCID: https://orcid.org/0000-0003-0741-2414)
- William L. Holland (ORCID: https://orcid.org/0000-0001-9950-1435)
- Chris Stubben (ORCID: https://orcid.org/0000-0002-3390-4888)
- Daisuke Shimura (ORCID: https://orcid.org/0000-0002-9954-2162)
- Sudipa Maity (ORCID: https://orcid.org/0000-0001-7717-3880)
- Tara R. Price (ORCID: https://orcid.org/0000-0001-6034-7952)
- Francisco Verdeguer (ORCID: https://orcid.org/0000-0002-5798-1503)
- Sandra Lee (ORCID: https://orcid.org/0000-0002-8198-0367)
- Jared Rutter (ORCID: https://orcid.org/0000-0002-2710-9765)
- Ademuyiwa S. Aromolaran (ORCID: https://orcid.org/0000-0002-3114-2939)
- Joel Zvick (ORCID: https://orcid.org/0000-0001-5877-2116)
- Sihem Boudina (ORCID: https://orcid.org/0000-0002-4711-1109)
- Emma C. Rekate
- Vishaka Vinod
- Dung M. Nguyen
- Hannah E. Duron
- Vu D Nguyen
- Ashley R. Bratt
- Sarah Franklin
- Devorah Stucki
- Adrian M Velarde
- Yasmin B Masini
- Neeraj K Rai
- Nicolas Hartel (ORCID: https://orcid.org/0000-0001-6191-9975)
- Vivek Garg
- David R. Eberhardt
- David Mollinedo
- Marcus G. Pezzolesi
- Kimberley J. Evason
- Kamrul H. Chowdhury
- Xue Yin
- Anshu Kumari
- Patrice N. Mimche
- Ryan Bia
- Andrea Corbin
Institutions
- University of Maryland, Baltimore (US)
- Howard Hughes Medical Institute (US)
- University of Utah (US)
- Huntsman Cancer Institute (US)
- Thermo Fisher Scientific (United States) (US)
- Inspire Institute (US)
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-08-25
- DOI
- https://doi.org/10.1172/jci204023
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Heart Association
- Barth Syndrome Foundation
- Nora Eccles Treadwell Foundation
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Arthritis and Musculoskeletal and Skin Diseases