ArticleNature chemical biology2026
SARM1 activation promotes axonal degeneration via a two-step phase transition.
Article in Nature chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The trial behind it
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Who cites it
8 citing papers in PubMed.
- Direct activation of SARM1 by dsDNA is not supported by biochemical and cellular evidence.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Peripheral Neuropathy in Metabolic Stress.International journal of molecular sciences · 2026Review
- Wallerian Degeneration and Nerve Regeneration-A Review of Cellular and Molecular Events.International journal of molecular sciences · 2026Review
- The rise and fall of SARM1 base-exchange inhibitors.Communications chemistry · 2026Article
- Plant NLRs are getting into higher-order architectures.The Plant journal : for cell and molecular biology · 2026Review
- Caspase-3 cleaves and activates the NADase SARM1 to promote apoptosis, linking two cell death mechanisms.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Interfering with GPX4 degradation.Nature chemical biology · 2025Article
- Therapeutic safety implications of SARM1 active site inhibitors: subinhibitory concentrations cause neurodegeneration.npj drug discovery · 2025Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
SARM1 is a key executioner of axonal degeneration, acting through NAD⁺ depletion by NADase activity of its TIR domain. Although normally autoinhibited, SARM1 becomes activated in response to axonal damage; however, the underlying mechanism remains unclear. Here, using a class of pyridine-containing compounds that trigger SARM1-dependent axon degeneration, we uncover a two-step activation process. First, NMN primes the base exchange activity of SARM1, generating covalent adducts between ADP-ribose (an NAD⁺ hydrolysis product) and the compounds. These ADP-ribose conjugates then serve as molecular glues to promote the assembly of superhelical SARM1 filaments, in which TIR domains adopt an active configuration. After reaching solubility limits, these filaments condense into stable, phase-separated assemblies with full enzymatic activity. Unexpectedly, several clinical-stage SARM1 inhibitors targeting its TIR domain also form such adducts, paradoxically promoting its activation. These findings reveal a molecular mechanism that spatially restricts SARM1 activation to damaged axons and offer new guidance for therapeutic strategies targeting SARM1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.