Core Viewpoint - The article discusses the role of SARM1 in axonal degeneration and its activation mechanism, highlighting its significance in neurodegenerative diseases and potential therapeutic strategies [2][7]. Group 1: Mechanism of SARM1 Activation - SARM1 is a key executor of axonal degeneration, activated through its TIR domain's NADase activity, leading to NAD⁺ depletion [2]. - The activation process involves NMN initiating SARM1's base exchange activity, forming covalent adducts with ADP-ribose, which promotes the assembly of superhelical SARM1 filaments [5]. - These filaments eventually coalesce into stable phase-separated assemblies with full enzymatic activity upon reaching a solubility limit [5]. Group 2: Implications for Therapeutic Strategies - The findings reveal a molecular mechanism that confines SARM1 activation to damaged axons, providing new insights for developing neuroprotective strategies targeting SARM1 [7]. - Interestingly, several clinical-stage inhibitors targeting the SARM1 TIR domain paradoxically promote its activation by forming similar adducts [6].