Vitamin K3 metabolic fate determines pro-survival or ferroptotic outcomes in multiple myeloma via UBIAD1 and reductase axis Free

While vitamin K1/K2 exert antioxidant effects that protect cancer cells from oxidative stress, The paradoxical role of vitamin K3 (menadione) in cancer—oscillating between antioxidant protection and cytotoxicity remains mechanistically unresolved. Here, we demonstrate that the functional duality of vitamin K3, which can promote antioxidant survival or trigger ferroptosis, is dictated by its metabolic fate.

Our experiments definitively demonstrate that vitamin K3 induces myeloma cell death through ferroptosis, as evidenced by three hallmark features: Lipid Peroxidation Surge: Treatment of MM1S cells with 20 μM vitamin K3 significantly elevated levels of malondialdehyde (MDA) by 3.2-fold and 4-hydroxynonenal (4-HNE) [specify fold-change or p-value if available], confirming profound lipid peroxidation. GPX4 Suppression: Vitamin K3 treatment markedly decreased GPX4 protein expression by 65%, compromising a key antioxidant defense and disrupting redox homeostasis. Ferroptosis Inhibitor Specificity: Cell death induction by vitamin K3 (78%) was significantly attenuated by the ferroptosis inhibitor Liproxstatin-1 (reduced to 32%; P<0.01), whereas apoptosis inhibitors failed to confer protection.

We establish that the functional duality of vitamin K3 is governed by its metabolic processing through UbiA prenyltransferase domain-containing protein 1 (UBIAD1) and reductase enzymes. Specifically, in MM1S myeloma cells, low-dose vitamin K3 (1 μM) is metabolized to vitamin K2 by UBIAD1, thereby augmenting cellular antioxidant capacity and rescuing cells from RSL3-induced ferroptosis. Critically, pharmacological or genetic inhibition of UBIAD1 abolished this protective effect, rendering cells susceptible to ferroptosis even at low vitamin K3 concentrations. Conversely, high-dose vitamin K3 (20 μM) directly induced ferroptosis independently of UBIAD1 activity.

The metabolic fate of vitamin K3 was dictated by cellular reductase expression profiles. Overexpression of two-electron reductases (e.g., FSP1, NQO1) in MM1S cells suppressed vitamin K3-driven ROS generation and ferroptosis. Conversely, single-electron reductases (e.g., CYB5R1, CYP450R-1/2) in HUVECs amplified oxidative stress and potentiated cell death. Mechanistically, single-electron reduction generates unstable semiquinone radicals, propagating lipid peroxidation—a hallmark of ferroptosis.

Clinical validation utilizing patient-derived organoids (PDOs) established from primary myeloma cells of 8 patients revealed that sensitivity to vitamin K3 correlated with low UBIAD1 expression and elevated levels of single-electron reductases. Transcriptomic analysis of PDOs derived from the 4 responding patients (4 of 8) confirmed the enrichment of ferroptosis-associated gene signatures following vitamin K3 treatment. Furthermore, in the exploratory investigator-initiated trial (IIT), administration of vitamin K3 to a patient with multiple myeloma relapsed after four prior lines of therapy resulted in partial remission, further supporting the clinical relevance of our mechanistic model.

Collectively, our findings demonstrate that the function of vitamin K3 is governed by a critical metabolic switch: UBIAD1-mediated conversion to vitamin K2 confers cytoprotection and enhances antioxidant capacity, whereas reductase-driven redox cycling generates oxidative stress and triggers ferroptosis.