HuD is an RNA-binding protein encoded by the ELAVL4 gene, which is expressed in the nervous system and plays a crucial role during nervous system development. However, recent evidence suggests its potential involvement in neurodegenerative processes, including Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease characterized by death of motoneurons (MNs). Notably, upregulation of both mRNA and protein levels of HuD has been observed in MNs derived from FUS P525L human induced pluripotent stem cells (hiPSCs) and in a Fus-Δ14 knock-in mouse model, impacting on MNs’ transcriptome and phenotype. HuD's gain-of-function effect also demonstrated to exacerbate cell-autonomous effects of the FUS P525L variant, leading to defects in Neuromuscular Junctions’ establishment and apoptosis phenomena, evident in co-cultures of hiPSC-derived MNs and skeletal muscle cells, with a rescue of both phenotypes after siRNA against HuD treatment. Moreover, RNA interference against the HuD-related gene elav in Drosophila model demonstrated to completely rescue the disfunctional motor phenotype induced by FUS P525L overexpression. Recent evidence also indicates a potential role for HuD in sporadic ALS. Specifically, HuD levels rise in response to oxidative stress in MNs derived from hiPSCs, and this phenomenon is also observed in sporadic ALS patients who exhibit an oxidative stress signature. Based on these findings we designed RNA-based teurapeutic molecules as siRNAs, miRNA mimics and Antisense Oligonucleotides gapmers that will be tested in FUS P525L MNs and MNs-SKMs co-cultures with the aim of reducing HuD’s levels obtaining a phenotypic rescue.