Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, clinically marked by muscle atrophy and weakness. Although the clinical course is highly variable, the average time from the onset of symptoms to the need for respiratory support or death is 3–5 years. ALS is the most prevalent motor neuron disease in adults, occurring at a rate of 2 per 100,000 individuals and affecting 5.4 per 100,000 individuals overall. At present, there is no established effective treatment for ALS; riluzole (an antagonist of glutamate neurotransmission) and edaravone (a superoxide scavenger) are the only drugs approved for use in the treatment of ALS, and both produce only slight beneficial effects in a limited population of ALS patients. Tofersen, a recently US Food and Drug Administrationapproved antisense oligonucleotide, is only for patients carrying SOD1 mutation (Mead et al., 2023). Despite ALS has a significant genetic component with high heritability, many gene variants responsible for or contributing to the disease remain unidentified. The involvement of numerous cellular processes in ALS progression complicates the identification of causative factors. The complexity of the disease and the extensive genetic and phenotypic diversity among patients hinder the translation of findings from animal models to successful human clinical trials. 5%–10% of ALS cases are classified as familial ALS based on family history. The genes most associated with familial ALS include C9ORF72, TARDBP, FUS, and SOD1. Recent genetic studies have identified various mutations in sporadic ALS cases, suggesting potential genetic contributors to the disease. These risk genes implicate pathways such as apoptosis due to mitochondrial dysfunction, autophagy with disrupted protein homeostasis, inflammation (both peripheral and central), impaired intracellular trafficking, and excitotoxicity. These dysfunctional pathways affect multiple cell types, including upper (corticospinal) and lower (spinal) motor neurons, associated glial and Schwann cells, skeletal muscle fibers and their progenitors, and immune/inflammatory cells.  Among the genes most specifically associated with ALS and muscle atrophy retrieved by BenevolentAI Knowledge Graph, of particular interest is signal transducer and activator of transcription-3 (STAT3), which is among the five genes contributing to common ALS disease mechanisms such as autophagy, apoptosis, cytokine signaling and the FOXO signaling pathway, underscoring the central role of STAT3 signaling in the disease. Furthermore, beyond inflammation, autophagy, apoptosis, and the FOXO pathways, Janus kinase (JAK)/STAT signaling is heavily implicated in the distinctive pathophysiology of ALS. This includes aspects such as TAR DNA-binding protein 43 (TDP-43) protein aggregation, mitochondrial dysfunction, skeletal muscle denervation, and excitotoxicity. These disease processes are widely recognized as major contributors to ALS pathology, particularly mitochondrial dysfunction leading to ATP deficits and protein aggregation, with TDP-43 aggregates present in 95% of patients, along with muscle denervation and atrophy culminating in fatality. The revelation that all these pathways involve JAK/ STAT signaling implies that targeting this pathway could hold therapeutic promise (Richardson et al., 2023).