In conclusion, our findings show that S100A4 plays an important role in ALS-related mechanisms, and suggest that the use of a pleiotropic compound such as niclosamide, capable of affecting inflammatory, autophagic, and profibrotic mechanisms in several tissues of an ALS model, can meet the requirements of a possible treatment for ALS, that necessarily must be multifunctional and multitarget. Here, S100A4 is linked to amyotrophic lateral sclerosis.