Reddy, B. A. | bioRxiv Science

bioRxiv2026

The vitamin K oxidoreductase VKORC1L1 prevents oxidative stress in hepatocytes and protects from MASLD and hepatocellular carcinoma

Generation of vitamin K hydroxyquinone (VKH2) by vitamin K oxidoreductase 1 (VKORC1) is essential for the {gamma}-carboxylation of clotting factors by hepatocytes. Here, we uncover a non-redundant function of the vitamin K oxidoreductase paralogue VKORC1L1 in liver homeostasis. Mice lacking Vkorc1l1 globally or specifically in hepatocytes exhibit normal coagulation yet develop progressive metabolic dysfunction-associated steatotic liver disease (MASLD). Transcriptomic profiling revealed early dysregulation of lipid metabolism and inflammatory pathways, converging on human MASLD signatures, while genetic colocalization analyses implicate human VKORC1L1 variants in MASLD and liver fat accumulation. Mechanistically, VKORC1L1 prevents reactive oxygen species overload and DNA damage through vitamin K reduction, independently of {gamma}-carboxylation. Loss of VKORC1L1 induces oxidative stress, chromosome instability, and aneuploidy, culminating in steatohepatitic hepatocellular carcinoma (HCC). Conversely, pharmacological vitamin K supplementation rescues oxidative stress, MASLD and DNA damage in Vkorc1l1-deficient mice. These findings redefine vitamin K as a hepatic antioxidant and identify VKORC1L1 as a safeguard against MASLD and HCC.

cancer biology↗

bioRxiv2025

Vitamin K-dependent carboxylation in osteoblasts regulates bone resorption through GAS6

Studies in humans suggest that vitamin K is involved in the regulation of bone remodeling, but the precise mechanism at play remains unknown. In cells, vitamin K functions as a co-factor for the {gamma}-glutamyl carboxylase (GGCX), an enzyme responsible for the conversion of glutamic acid residues (Glu) into {gamma}-carboxyglutamic acid (Gla) residues in secreted proteins. We aim here at determining the role of {gamma}-carboxylation in bone remodeling and at identifying the Gla protein(s) involved. We show that male mice lacking {gamma}-carboxylation specifically in osteoblasts (Ggcxflox/flox;OCN-Cre) have increased bone mass at 6 months of age due to a reduced number of multinucleated bone resorbing osteoclasts. In co-culture experiments, Ggcx-deficient osteoblasts were less effective than control osteoblasts at supporting osteoclast formation. Among known Gla proteins, we identify GAS6 as an osteoblast-secreted {gamma}-carboxylated factor which signals to differentiating osteoclasts. The GAS6 receptors MerTK and AXL are expressed in pre-osteoclasts and pharmacological inhibitors of AXL and MerTK block osteoclast generation in co-culture. Conversely, recombinant {gamma}-carboxylated GAS6 dose-dependently increases the size of osteoclasts and the number of nuclei per osteoclast in culture. GAS6 marginally affected the induction of osteoclast-specific genes during osteoclast differentiation but significantly increased pre-osteoclast fusion. Finally, increasing bone marrow GAS6 level in transgenic male mice was sufficient to increase the number and size of osteoclasts and to decrease bone mass. This work identifies GAS6 as a novel osteoblast-derived vitamin K-dependent protein regulating osteoclast maturation.

cell biology↗