A Neutrophil Defensin–VDAC1 Axis Drives Steatotic Liver Disease
Year: 2026
Type: preprint
Abstract: ABSTRACT Neutrophils infiltrate the liver as metabolic dysfunction-associated steatotic liver disease (MASLD) progresses from simple steatosis to steatohepatitis, but whether neutrophil effectors merely mark this transition or cause it is unknown. Here we show that human neutrophil peptides (HNPs), or α-defensins, are drivers rather than bystanders of disease. In patients surgically treated for hepatic hemangioma who displayed overt MASLD, the abundance of HNPs in their liver biopsy samples localized to diseased tissue correlates with the histological severity of steatosis. In vitro, HNPs enter hepatocytes to induce multimerization of voltage-dependent anion channel 1 (VDAC1) in the mitochondrial outer membrane, causing mitochondrial dysfunction and lipid accumulation. Under lipid overload, but not on a standard diet, HNP1-transgenic mice develop increased adiposity and steatohepatitis, which is reversed by an orally available prodrug that inhibits HNP-induced VDAC1 multimerization. These findings link neutrophil innate immunity to hepatocyte mitochondrial dysfunction, recast host-protective HNPs as pathogenic effectors when hepatocyte mitochondria are lipid-burdened, and establish the HNP–VDAC1 axis as a therapeutic target in MASLD.
Authors: Jue Zhang, Gan Luo, Gang Wang, Jie Rao, Xiao Li, Wuyuan Lu
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214300461