Excessive Ca <sup>2+</sup> -dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury
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, <i>EF-Hand Domain Family Member D1</i> (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca<sup>2+</sup>-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca<sup>2+</sup> 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-dependent 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 Ca<sup>2+</sup>-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)
- Vivek Garg (ORCID: https://orcid.org/0000-0002-6940-5415)
- Enrique Balderas (ORCID: https://orcid.org/0000-0001-8780-9272)
- David Eberhardt (ORCID: https://orcid.org/0000-0002-6538-8611)
- Dipayan Chaudhuri (ORCID: https://orcid.org/0000-0003-0605-7334)
- Sarah Franklin (ORCID: https://orcid.org/0000-0002-2958-1879)
- Scott A. Summers (ORCID: https://orcid.org/0000-0002-4919-0592)
- Robin M. Shaw (ORCID: https://orcid.org/0000-0001-7429-6092)
- Nicolas G. Hartel (ORCID: https://orcid.org/0000-0001-6191-9975)
- Anthony M. Balynas (ORCID: https://orcid.org/0000-0003-0741-2414)
- 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)
- Ryan Bia (ORCID: https://orcid.org/0000-0002-1979-7051)
- Patrice N. Mimche (ORCID: https://orcid.org/0000-0002-3761-7237)
- Emma C. Rekate
- Vishaka Vinod
- Andrea Corbin (ORCID: https://orcid.org/0000-0003-2626-834X)
- Kamrul Hasan Chowdhury
- Dung M. Nguyen (ORCID: https://orcid.org/0000-0001-8720-6420)
- Hannah E. Duron
- David M. Mollinedo
- Joel Zvick
- Vu D Nguyen
- Ademuyiwa S. Aromolaran (ORCID: https://orcid.org/0000-0003-3745-9213)
- Ashley R. Bratt
- W L Holland
- Jared Rutter
- Xue Yin
- Devorah Stucki
- Kimberley J Evason
- Adrian M Velarde
- Yasmin B Masini
- Neeraj K Rai
- Anshu Kumari
- Marcus G Pezzolesi
Institutions
- University of Maryland, Baltimore (US)
- Howard Hughes Medical Institute (US)
- University of Utah (US)
- Huntsman Cancer Institute (US)
- Inspire (CH)
- Thermo Fisher Scientific (United States) (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-02-16
- DOI
- https://doi.org/10.64898/2026.02.13.705622
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Thomas Jefferson University
- Huntsman Cancer Institute