NAPRT loss promotes lung tumor initiation and growth through AKT signaling independently of NAD ⁺

Nicotinamide adenine dinucleotide (NAD ⁺ ) metabolism is frequently rewired in cancer, creating metabolic vulnerabilities that can be therapeutically exploited. Loss of nicotinate phosphoribosyltransferase (NAPRT), a rate‐limiting enzyme of the Preiss–Handler pathway, renders tumor cells dependent on nicotinamide phosphoribosyltransferase (NAMPT)‐mediated NAD ⁺ synthesis and serves as a predictive biomarker for NAMPT inhibitor sensitivity. However, whether NAPRT loss actively contributes to tumorigenesis remains unclear. Here, we show that NAPRT depletion promotes tumorigenic phenotypes in lung cancer through a noncanonical mechanism independent of NAD ⁺ biosynthesis. NAPRT knockdown enhanced clonogenic initiation, sphere formation, and invasive capacity. Mechanistically, NAPRT loss drives mTORC2‐dependent activation of the AKT signaling axis. This effect was not reversed by nicotinic acid or NAD ⁺ supplementation or recapitulated by catalytic inhibition of NAPRT, indicating a function distinct from its metabolic role. Pharmacologic AKT inhibition attenuated the enhanced growth induced by NAPRT depletion. In vivo , lung‐specific Naprt deletion significantly increased tumor burden in Kras ^G12D ‐driven mice without altering tumor histology or immune cell composition. Together, these findings identify a previously unrecognized tumor‐suppressive role for NAPRT in lung tumor initiation and growth.