ArticleThe Journal of clinical investigation2026
Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.
Article in The Journal of clinical investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Metabolic dysfunction-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 showed that EFHD1, a Ca2+-dependent actin cross-linker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS) by detecting spatiotemporal coincidence of interorganellar 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, protein kinase RNA-activated-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.
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