2. Academic Validation
  3. SARM1 senses dsDNA to promote NAD+ degradation and cell death

SARM1 senses dsDNA to promote NAD+ degradation and cell death

  • Cell. 2025 Oct 24:S0092-8674(25)01126-2. doi: 10.1016/j.cell.2025.09.026.
Lina Wang 1,  Qiaoling Liu 2,  Siru Li 2,  Na Wang 2,  Yan Chen 3,  Junren Chen 2,  Li Wang 4,  Yuelin Huang 5,  Zhen Sun 2,  Ling Dong 2,  Shao Li 5,  Quentin Liu 3,  Song Gao 3,  Xiaochi Ma 6,  Chengli Song 7,  Qingkai Yang 8
Affiliations

Affiliations

  • 1 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China; Department of Cancer Research, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, China.
  • 2 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.
  • 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China.
  • 4 CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
  • 5 Department of Physiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China.
  • 6 Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116044, China.
  • 7 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China. Electronic address: songchengli@dmu.edu.cn.
  • 8 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China. Electronic address: yangqingkai@dmu.edu.cn.
PMID: 41138726 DOI: 10.1016/j.cell.2025.09.026
Abstract

Detection of DNA is a fundamental strategy for life to recognize non-self or abnormal-self to subsequently trigger the downstream responses. However, the mechanism underlying DNA sensing is incompletely understood. Here, we show that a key neural executioner, sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), senses double-stranded DNA (dsDNA) to promote cell death. dsDNA-bound and -activated SARM1 to degrade nicotinamide adenine dinucleotide (NAD+) in a sequence-independent manner. SARM1 bound dsDNA via the TIR domain, and lysine residues in the TIR domain contributed to dsDNA binding. In the cellular context, cytosolic dsDNA from dsDNA transfection or chemotherapy treatment was colocalized with SARM1 and activated SARM1 to elicit NAD+ degradation and cell death, which was abrogated by SARM1 knockout or DNA-binding residue mutation. Consistently, SARM1 knockout blocked chemotherapy-induced neuropathy (CIN) in mice. Our results reveal SARM1 as a DNA sensor, which might be targetable for therapeutic interventions.

Keywords

CIN; DNA sensor; NAD; SARM1; TIR domain; axon degeneration; cancer; cell death; chemotherapy-induced neuropathy; metabolism.

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