Abstract Aim Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A‐1, a derivative of arctigenin with AMP‐activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated. Methods A‐1 at 33.3 mg/kg was administrated in SOD1 G93A transgenic mice orally from the 13th week for a 6‐week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&amp;E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Results A‐1 administration in SOD1 G93A mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A‐1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial‐related proteins. The A‐1 treatment group showed decreased levels of IL‐1β, pIκBα/IκBα, and pNF‐κB/NF‐κB. Conclusions A‐1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC‐1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL‐1β/NF‐κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A‐1 as a promising therapeutic approach for ALS.

Arctigenin derivative A‐1 ameliorates motor dysfunction and pathological manifestations in <scp>SOD1<sup>G93A</sup></scp> transgenic mice via the <scp>AMPK</scp>/<scp>SIRT1</scp>/<scp>PGC</scp>‐1α and <scp>AMPK</scp>/<scp>SIRT1</scp>/<scp>IL</scp>‐1β/<scp>NF‐κB</scp> pathways

Arctigenin derivative A‐1 ameliorates motor dysfunction and pathological manifestations in SOD1G93A transgenic mice via the AMPK/SIRT1/PGC‐1α and AMPK/SIRT1/IL‐1β/NF‐κB pathways