In this study, we have analyzed the role of S100A4 in cellular pathways linked to human ALS-fibroblasts activation, such as mTOR, sequestosome 1 (SQSTM1/p62), NF-κB, α-smooth muscle actin (α-SMA), and N-cadherin. This evidence concerns the gene ACTA1 and amyotrophic lateral sclerosis.