A Neutrophil Defensin-VDAC1 Axis Drives Steatotic Liver Disease
- 1Fudan University
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 alpha-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.
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BibTeX
@misc{zhang2026neutrophil,
title = {{A Neutrophil Defensin-VDAC1 Axis Drives Steatotic Liver Disease}},
author = {J. Zhang and G. Luo and G. Wang and J. Rao and X. Li and W. Lu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.19.752841},
url = {https://www.biorxiv.org/content/10.64898/2026.09.19.752841v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Neutrophil Defensin-VDAC1 Axis Drives Steatotic Liver Disease
AU - J. Zhang
AU - G. Luo
AU - G. Wang
AU - J. Rao
AU - X. Li
AU - W. Lu
PY - 2026
DA - 2026/09/19
PB - bioRxiv
DO - 10.64898/2026.09.19.752841
UR - https://www.biorxiv.org/content/10.64898/2026.09.19.752841v1
AB - 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 alpha-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.
ER -