Los Angeles – A gene located on the X chromosome, known as Kdm6a, may play a significant role in why women are disproportionately affected by multiple sclerosis (MS) and potentially other neurological conditions, according to new research from the University of California, Los Angeles. The findings, published in the journal Science Translational Medicine in 2025, shed light on the complex interplay between genetics, sex, and autoimmune disease. Understanding the role of Kdm6a could open new avenues for treatment and prevention, particularly for women facing a higher risk of these debilitating illnesses.
For decades, scientists have observed a clear disparity in the prevalence of autoimmune diseases, with women experiencing them at a rate two to three times higher than men. UCLA Health researchers have now pinpointed a potential biological mechanism driving this difference, focusing on the function of the Kdm6a gene and its impact on brain inflammation.
The Kdm6a gene codes for a histone demethylase, an enzyme that modifies gene activity. Because females have two X chromosomes, they have a “double dose” of this gene compared to males, leading to increased expression of the KDM6A protein. This heightened expression appears to drive inflammation in brain immune cells, called microglia, a key factor in the development of MS and Alzheimer’s disease, as well as contributing to “brain fog” experienced by many women during menopause, according to Dr. Rhonda Voskuhl, director of the Multiple Sclerosis Program at UCLA Health and lead neurologist for the UCLA Comprehensive Menopause Program.
The Link Between Kdm6a and Multiple Sclerosis
The UCLA team’s research utilized a mouse model of multiple sclerosis to investigate the role of Kdm6a. Deleting the Kdm6a gene in microglia of female mice led to a significant reduction in MS-like disease and associated neurological damage. Published in PubMed, the study details how this deletion shifted inflammatory molecules from an activated to a resting state, effectively calming the immune response in the brain. Interestingly, the same deletion had a much smaller effect in male mice, highlighting the gene’s sex-specific impact.
Further bolstering these findings, researchers discovered that metformin, a commonly used diabetes medication, also blocks the activity of KDM6A. When administered to female mice with MS, metformin ameliorated the disease, again normalizing the inflammatory response in microglia. Still, metformin showed limited efficacy in male mice, reinforcing the connection between Kdm6a, female biology, and autoimmune disease susceptibility.
How Kdm6a Influences Brain Inflammation
The researchers employed a technique called CUT&RUN, combined with sequencing analysis, to identify the specific genes bound by KDM6A within microglia. This revealed a direct link between the protein’s binding sites and changes in gene expression. Transcriptomic analysis of human microglia confirmed that women exhibit higher levels of KDM6A compared to men, and that a greater number of microglial genes are dysregulated in women with MS. This suggests that the increased KDM6A activity in women may contribute to a more pronounced inflammatory response in the brain, increasing their vulnerability to MS.
“It has long been known that We find sex differences in the brain,” Dr. Voskuhl stated. “These can impact both health and neurological diseases.” The study’s findings provide a crucial piece of the puzzle, explaining why women are more susceptible to MS and Alzheimer’s disease, and potentially offering a new target for therapeutic intervention.
Implications for Alzheimer’s Disease and Beyond
While the initial research focused on multiple sclerosis, the implications extend to other neurological conditions where inflammation plays a significant role. Alzheimer’s disease, for example, also affects women more frequently than men. The researchers believe that the Kdm6a-driven inflammatory pathway could be a common thread linking these diseases, opening the door to potential treatments that target this pathway across a range of neurological disorders.
The study also offers a potential explanation for the phenomenon of “brain fog” often experienced by women during menopause. Hormonal changes during menopause can influence immune function and inflammation, and the increased KDM6A activity may exacerbate these effects, contributing to cognitive difficulties.
Future Research and Potential Therapies
The UCLA team is now focused on further investigating the mechanisms by which Kdm6a regulates inflammation in the brain. They are also exploring the potential of metformin and other KDM6A inhibitors as therapeutic agents for MS and other neurological diseases. Clinical trials will be necessary to determine the safety and efficacy of these treatments in humans.
The discovery of Kdm6a’s role in sex-specific brain inflammation represents a significant step forward in our understanding of autoimmune diseases. By targeting this gene and its associated pathway, researchers hope to develop more effective treatments and ultimately reduce the burden of these debilitating conditions, particularly for women.
Researchers will continue to analyze data from the study and explore potential therapeutic interventions. The next phase of research will focus on translating these findings into clinical trials to assess the effectiveness of KDM6A inhibitors in human patients.
This research offers a new perspective on the complex interplay between genetics, sex, and neurological disease. If you or someone you grasp is affected by multiple sclerosis or Alzheimer’s disease, please consult with a healthcare professional for accurate diagnosis and treatment options. Share this article to assist raise awareness about the importance of sex-specific research in neurological disorders.
Disclaimer: This article provides information for general knowledge and informational purposes only, and does not constitute medical advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
