Sterile alpha and TIR motif-containing protein 1 (SARM1) is a multifunctional NAD⁺ hydrolase encoded by the SARM1 gene and belongs to the TIR domain-containing protein family. SARM1 is highly expressed in the nervous system and is particularly enriched in neuronal axons, where it serves as a central executor in response to neuronal injury, metabolic stress, and multiple neurodegenerative pathological processes ^[1]. SARM1 functions as a metabolic sensor that specifically recognizes and responds to abnormal elevations in the intracellular nicotinamide mononucleotide (NMN) to NAD⁺ ratio. It plays a critical regulatory role in Wallerian-like programmed axonal death triggered by neuronal injury. This process is closely associated with axonal injury, neurodegenerative diseases such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), as well as chemotherapy-induced peripheral neuropathy (CIPN) ^[2-4]. Studies have shown that pathogenic or gain-of-function variants of SARM1 can trigger uncontrolled NAD⁺ depletion, neuronal metabolic failure, and axonal degeneration ^[4]. SARM1 gene knockout or functional inhibition significantly protects axons from degeneration in various neuronal injury models ^[1]. Owing to its low-to-moderate expression in normal adult tissues and high expression in the nervous system, SARM1 has become an important therapeutic target in the field of neuroprotection. Multiple small-molecule inhibitors targeting SARM1, gene therapy strategies, and related drug candidates have entered preclinical and early clinical development for blocking programmed axonal degeneration and associated neuroinflammatory processes ^[5-7]. The hSARM1 mouse is a humanized model generated by replacing a partial sequence of exon 1 in the murine Sarm1 gene with the Kozak-Human SARM1 CDS-Human SARM1 3'UTR-WPRE-BGH pA cassette. This model is suitable for the in vivo efficacy and safety evaluation of SARM1-targeted small-molecule inhibitors, antisense oligonucleotides (ASOs), AAV-mediated gene silencing strategies, and other neuroprotective agents. It is also suitable for research on the mechanisms underlying axonal degeneration and neurodegenerative diseases, neuronal metabolic stress, and the regulation of the SARM1-NAD⁺ signaling pathway.

Tle6 is located on chromosome 10 of mice. Nuclease Technology will be used to design sgRNA; Tle6 knockout mice will be obtained by applying high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.