Res Sq [Preprint]. 2025 Aug 27:rs.3.rs-7014857. doi: 10.21203/rs.3.rs-7014857/v1.
ABSTRACT
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally. Disruptions in iron metabolism and mitochondrial oxidative function may cooperatively contribute to its pathogenesis. Ferredoxin reductase (FDXR), a mitochondrial flavoprotein, plays a critical role in mitochondrial respiratory supercomplex formation and iron-sulfur cluster biosynthesis-both essential for efficient oxidative metabolism. However, its role in MASLD remains unclear. Here, we knocked down hepatic Fdxr expression in the liver of C57BL/6 mice using N -acetyl galactosamine-conjugated antisense oligonucleotides. [ 13 C 5 ]glutamine tracer infusions revealed that FDXR deficiency disrupted mitochondrial oxidative phosphorylation. In contrast, FDXR deficiency increased hepatic iron accumulation, reactive oxygen species, and lipid peroxidation. Mechanistically, FDXR deficiency disrupted iron-sulfur cluster assembly and reduced mitochondrial proteins such as succinate dehydrogenase complex iron-sulfur subunit B (SDHB), leading to mitochondrial dysfunction and steatosis. FDXR expression was upregulated in both human and murine MASLD livers, suggesting a compensatory protective response. Furthermore, hepatic overexpression of FDXR restored mitochondrial function, enhanced oxidative capacity, and ameliorated steatosis. These findings identify FDXR as a key regulator linking iron metabolism and mitochondrial integrity in MASLD and highlight its potential as a therapeutic target to prevent disease progression.
PMID:40909793 | PMC:PMC12408023 | DOI:10.21203/rs.3.rs-7014857/v1