X chromosome-encoded microRNAs in immune regulation: sex differences and clinical implications

Sex-based differences in immune function influence susceptibility to infections and predisposition to autoimmunity, with women showing both stronger immune responses and a higher burden of autoimmune and chronic inflammatory diseases. While sex hormones contribute to these differences, accumulating evidence highlights a central role for the X chromosome, which is enriched in immune-related genes and subject to complex regulatory mechanisms such as X-chromosome inactivation, skewing, escape from inactivation, and imprinting. Within this context, X chromosome-encoded microRNAs (miRNAs) have emerged as key post-transcriptional regulators of immune homeostasis. The X chromosome harbors the highest density of miRNAs in the human genome, many of which target pathways involved in immune activation, tolerance, and tumorigenesis. Notably, some X-resident miRNAs escape X-chromosome inactivation, leading to female-biased expression that may enhance immune reactivity but also predispose to loss of tolerance and autoimmunity. In this minireview, we summarize current knowledge on X chromosome-encoded miRNAs in immune regulation, discuss how their sex-biased expression patterns may contribute to female predominance in autoimmune diseases, and explore their potential utility as biomarkers and therapeutic targets for sex-aware precision medicine in inflammatory, autoimmune disorders and vaccine responses.