02584nas a2200349   4500000000100000000000100001008004100002260001500043653001700058653002600075653002500101100002500126700002300151700002300174700002200197700002200219700002600241700002900267700002000296700001500316700001800331700002200349700001700371700002200388700002100410700003300431245006500464856005500529300000900584520162700593022001402220       2025                            d  c2025-10-1310aCell biology10aCellular neuroscience10aScientific community1 aLaura Castro-Aldrete1 aMelanie Einsiedler1 aCarla Cuní-López1 aQuentin Vanhaelen1 aAntonia Silvestri1 aMaria Teresa Ferretti1 aMartina Elena de Gennaro1 aGuido Putignano1 aMaria Guix1 aNicola Marino1 aLiisa A. M. Galea1 aKerstin Lenk1 aSamantha Paoletti1 aAlex Zhavoronkov1 aAntonella Santuccione Chadha00aModelling sex differences of neurological disorders in vitro  uhttps://www.nature.com/articles/s44222-025-00355-w  a1-223 aAlthough in vitro models are valuable tools for modelling neurological disorders such as neurodegenerative diseases and neuropsychiatric disorders, it remains unclear whether and how biological sex characteristics should be considered when designing experiments. The historical failure to incorporate sex as a biological variable and acknowledge sex and gender differences in preclinical and clinical research has created a translation gap, which is only now beginning to be addressed. Sex effects are observed across mechanisms in common neuropsychiatric and neurodegenerative disorders. Therefore, it is imperative to incorporate sex differences into both in vitro and in vivo models to develop more precise and sustainable research tools for brain disorders. Such an approach will enable researchers to account for the physiological and pathological characteristics of male and female brains, improving the replicability and translatability of research results. In this Review, we discuss in vitro models of increasing complexity used for exploring pathological mechanisms and pharmacological target development. We address the advantages and challenges of using in vitro models to investigate sex differences in neurological disorders, starting with the types of cells used in in vitro models, including immortalized cell lines, primary cultures, induced pluripotent stem cells, up to 3D organoid and organ-on-a-chip models. Furthermore, we propose a roadmap and discussion of best practices to incorporate sex as a biological variable into in vitro models of neurodegenerative diseases and neuropsychiatric disorders.  a2731-6092