Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.

Impaired NAD⁺ regeneration via the mevalonate pathway reduces serine biosynthesis by 50% and increases neuroblastoma cell sensitivity to PHGDH inhibition.

• Why it matters: Understanding how cancer cells sustain amino acid and nucleotide production reveals vulnerabilities that can be exploited for therapy, especially in tumors with high mevalonate pathway activity.
• What they did: The study used statins to inhibit the mevalonate pathway in neuroblastoma cells, combined with genetic and pharmacological methods to disrupt ubiquinone synthesis, and tested NADH oxidase LbNOX to restore NAD⁺ levels, assessing effects on metabolism and growth.
• The result: Findings show that blocking NAD⁺ regeneration hampers serine and nucleotide synthesis, sensitizing cells to PHGDH inhibitors, and combining statins with NCT-503 significantly enhances anti-tumor effects, suggesting a promising therapeutic strategy.