XIST, a long non-coding RNA, typically spreads across the X chromosome to mediate gene silencing during X chromosome inactivation (XCI). However, in female naive human pluripotent stem cells (hPSCs), XIST exhibits a dispersed configuration and spreads beyond the X chromosome to downregulate gene expression on autosomes. This study reveals that XIST targets specific autosomal regions, inducing repressive chromatin changes and gene expression dampening. XIST-mediated gene dampening equalizes X-linked gene dosage between males and females while inducing differences in autosomal gene expression. The dispersed XIST configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. These findings identify XIST as a regulator of X chromosome dampening and uncover its evolutionarily conserved trans-acting role, linking XIST dispersal to autosomal targeting.XIST, a long non-coding RNA, typically spreads across the X chromosome to mediate gene silencing during X chromosome inactivation (XCI). However, in female naive human pluripotent stem cells (hPSCs), XIST exhibits a dispersed configuration and spreads beyond the X chromosome to downregulate gene expression on autosomes. This study reveals that XIST targets specific autosomal regions, inducing repressive chromatin changes and gene expression dampening. XIST-mediated gene dampening equalizes X-linked gene dosage between males and females while inducing differences in autosomal gene expression. The dispersed XIST configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. These findings identify XIST as a regulator of X chromosome dampening and uncover its evolutionarily conserved trans-acting role, linking XIST dispersal to autosomal targeting.