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<p>Nicotinamide adenine dinucleotide (NAD) is synthesized through both amidated salvage and deamidated pathways. Although NAD-producing enzymes are often overexpressed in cancer cells to meet the high metabolic demands of rapid proliferation and are considered oncogenic, we report that physiological levels of nicotinic acid phosphoribosyl transferase (NAPRT), the first enzyme in the Preiss-Handler arm of the deamidated pathways, suppress tumorigenesis. We show that NAPRT is enriched in gut epithelial cells, where it sustains the NAD pool for an efficient response to stress-induced acute NAD depletion. Consequently, NAPRT deficiency impairs the activity of poly-(ADP-ribose) polymerases and DNA repair, sensitizes mice to chemical-induced colitis and tumorigenesis, as well as to age-associated spontaneous tumor development. Moreover, low NAPRT expression correlates with poor prognosis in several human cancer types. Thus, homeostatic levels of deamidated NAD biosynthesis contribute to tumor suppression, and boosting this pathway may offer a strategy for cancer prevention.</p>

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NAPRT-mediated deamidated NAD biosynthesis enhances colon tissue resiliency and suppresses tumorigenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月10日

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  • Xiaoyue Wu,
  • Jason G. Williams,
  • Haoyang Liang,
  • Artiom Gruzdev,
  • Joshua Hartsell,
  • Jack Shpargel,
  • Rabina Mainali,
  • Yi Fang,
  • Ming Ji,
  • Caroline Duval,
  • Xin Xu,
  • Zixin Zhang,
  • Heather Winter,
  • Peter Pediaditakis,
  • Arun R. Pandiri,
  • Marie E. Migaud,
  • Alan K. Jarmusch,
  • Huimin Yu,
  • Xiaojing Liu,
  • Jian-Liang Li,
  • Xiaojiang Xu,
  • Igor Shats,
  • Xiaoling Li

摘要

Nicotinamide adenine dinucleotide (NAD) is synthesized through both amidated salvage and deamidated pathways. Although NAD-producing enzymes are often overexpressed in cancer cells to meet the high metabolic demands of rapid proliferation and are considered oncogenic, we report that physiological levels of nicotinic acid phosphoribosyl transferase (NAPRT), the first enzyme in the Preiss-Handler arm of the deamidated pathways, suppress tumorigenesis. We show that NAPRT is enriched in gut epithelial cells, where it sustains the NAD pool for an efficient response to stress-induced acute NAD depletion. Consequently, NAPRT deficiency impairs the activity of poly-(ADP-ribose) polymerases and DNA repair, sensitizes mice to chemical-induced colitis and tumorigenesis, as well as to age-associated spontaneous tumor development. Moreover, low NAPRT expression correlates with poor prognosis in several human cancer types. Thus, homeostatic levels of deamidated NAD biosynthesis contribute to tumor suppression, and boosting this pathway may offer a strategy for cancer prevention.