02016nas a2200217   4500000000100000000000100001008004100002260001500043653003400058653002200092100002100114700003800135700002000173700002300193700001900216245008800235856005500323300000900378520139700387022001401784       2026                            d  c2026-07-0610aamyotrophic lateral sclerosis10aNeural Stem Cells1 aBenedetta Frizzi1 aAdriana Margarida Barbosa Correia1 aIrene Faravelli1 aLudo Van Den Bosch1 aStefania Corti00aUsing human 3D organoid models to gain mechanistic insight in motor neuron diseases  uhttps://www.nature.com/articles/s41583-026-01057-x  a1-213 aMotor neuron diseases (MNDs) are caused by the progressive loss of motor neurons and eventually lead to paralysis and death. Once viewed as primarily neurocentric, MNDs are now recognized to be driven by intertwined cell-autonomous and non-cell-autonomous mechanisms. Dissecting these interactions is essential for developing effective therapies. Here, we describe induced pluripotent stem cell-derived 3D models that can be used to capture distinct aspects of MND pathology. We show that spinal cord organoids can be used to investigate cell-autonomous mechanisms and motor neuron–glia interactions (with axially elongated spinal cord organoids being particularly useful to study developmental vulnerability) as well as in 3D muscle and combined neuromuscular models to dissect muscle pathology and neuromuscular junction dismantling. In parallel, we discuss advances in bioengineering, machine learning and human trunk-like models, which together can begin to reproduce the coordinated co-development and spatial organization of the multiple tissues affected in MNDs. We discuss how these systems have advanced our understanding of disease mechanisms and highlight opportunities for drug repurposing. Finally, we propose a mechanism-informed and phenotype-informed framework to guide 3D model selection for future research and to prioritize promising avenues for therapeutic development.  a1471-0048