LSD1 is an enzyme that removes chemical tags from proteins in your cells, acting as a master switch for turning genes on and off. Discovered in 2004, it was the first enzyme ever found to reverse a type of gene modification that scientists had long assumed was permanent. Its official gene name is KDM1A, located on chromosome 1, and it has become one of the most studied targets in cancer research because of its outsized role in controlling cell growth, brain development, and disease.
The First Histone Demethylase
Your DNA doesn’t float loosely inside cells. It wraps tightly around spool-like proteins called histones, and small chemical groups attached to those histones determine whether nearby genes are accessible or locked away. One of these chemical groups is a methyl tag. For decades, scientists believed that once a methyl tag was added to a histone, it stayed there permanently. That changed in 2004 when Yang Shi’s laboratory identified an enzyme, originally called nPAO, that could strip methyl tags off histones. The enzyme was renamed LSD1, short for lysine-specific histone demethylase 1, and its discovery opened an entirely new field. More than 20 similar enzymes have been identified since.
How LSD1 Works
LSD1 relies on a helper molecule called FAD (a derivative of vitamin B2) to carry out its chemical reaction. The process works like a controlled oxidation: LSD1 pulls electrons away from the methyl-tagged amino acid on the histone, creating an unstable intermediate that quickly breaks apart in water. The methyl group leaves as formaldehyde, and the FAD molecule recharges itself using oxygen, producing a small amount of hydrogen peroxide as a byproduct.
This mechanism has one important limitation. LSD1 can only remove one or two methyl tags from a single site, not three. Histones with three methyl tags require a different family of enzymes (the JmjC family) to handle the job. Together, these two enzyme families can reverse methylation at nearly every major site on histones, giving cells remarkable flexibility in reprogramming their gene activity.
Turning Genes On and Off
LSD1’s effect on gene activity depends on where it acts. Its primary target is a spot called H3K4, a position on histone H3 where methyl tags normally signal that a gene should be active. When LSD1 strips those tags away, the gene quiets down. This makes LSD1 a transcriptional repressor in most contexts.
But LSD1 can also activate genes. When it targets a different spot called H3K9, where methyl tags typically silence genes, removing those tags turns genes back on. A specialized version of LSD1, created by alternative splicing of its gene, preferentially demethylates H3K9 rather than H3K4. This variant, called LSD1+8a, plays a key role in neurons and is essential for proper brain cell development.
LSD1 Doesn’t Work Alone
Inside cells, LSD1 rarely acts as a solo operator. It typically functions as part of a larger protein machine called the CoREST complex. This complex is notable because it bundles two different types of gene-silencing activity into one unit: LSD1 removes methyl tags while a partner enzyme called HDAC1 removes a different type of chemical tag (an acetyl group). A bridging protein, RCOR, physically links the two enzymes together. The CoREST complex was originally identified as a key silencer of neuronal genes in non-neuronal cells, working with a master regulator called REST that keeps brain-specific genes turned off in tissues where they don’t belong.
Beyond Histones
LSD1 doesn’t limit itself to modifying histones. It also removes methyl tags from at least nine other proteins in the cell, altering their stability or activity. The tumor suppressor p53, one of the most important cancer-preventing proteins in the body, was the first non-histone target identified. LSD1 demethylates p53 at a specific site, which dampens its ability to activate protective genes. This is one reason LSD1 overactivity can be so dangerous in cancer cells.
Other targets include E2F1 (a protein that drives cell division, which LSD1 stabilizes), HIF-1α (a protein that helps cells survive low-oxygen conditions, also stabilized by LSD1), and STAT3 (a signaling protein whose gene-activating ability increases after LSD1 removes its methyl tags). These non-histone functions help explain why LSD1 influences so many different cellular processes and why blocking it has such wide-ranging effects.
Role in Brain Development
LSD1 is essential for the brain. In human neural stem cells, LSD1 activity is required for those stem cells to mature into functioning neurons. When researchers block LSD1 in fetal neural stem cells, the cells keep dividing as immature progenitors instead of differentiating into neurons. The neuron-specific variant LSD1+8a is particularly important here: it works with a partner protein called supervillin to remove silencing marks from genes that neurons need to function, and losing this variant compromises neuronal differentiation.
There are also intriguing connections to neurodevelopmental conditions. In animal models of autism related to the Shank3 gene, inhibiting LSD1 with a targeted drug rescued social deficits and behavioral symptoms, suggesting that LSD1’s gene-regulatory activity intersects with pathways involved in social behavior.
LSD1 and Cancer
LSD1 is overproduced in many cancers, and higher levels generally predict worse outcomes. Elevated LSD1 has been linked to poor prognosis in cancers of the lung, liver, colon, esophagus, and breast. In basal-like breast cancer (an aggressive subtype), patients with high LSD1 expression had a hazard ratio of 4.3 for recurrence, meaning they were more than four times as likely to see their cancer return. In triple-negative breast cancer specifically, high LSD1 protein levels served as a reliable marker of poor outcomes.
At the cellular level, LSD1 promotes three hallmarks of aggressive cancer: rapid proliferation, resistance to cell death, and epithelial-to-mesenchymal transition, the process by which stationary cells gain the ability to migrate and invade other tissues. Its demethylation of p53 further tips the balance by weakening one of the cell’s main tumor-suppressing mechanisms.
LSD1 As a Drug Target
Because LSD1 is overactive in so many cancers, pharmaceutical companies have developed drugs that block it. The therapeutic concept is especially compelling in acute myeloid leukemia (AML), where LSD1 inhibition triggers a fundamentally different approach to treatment. Rather than killing cancer cells with toxic chemotherapy, blocking LSD1 coaxes immature leukemia cells into finishing their development into normal blood cells, a strategy called differentiation therapy. This works in part by disrupting LSD1’s interaction with a protein called GFI1, which normally helps keep leukemia cells locked in their immature, rapidly dividing state.
The most advanced LSD1 inhibitor in clinical development is bomedemstat, which has reached phase 3 trials for essential thrombocythemia, a blood disorder involving overproduction of platelets. In earlier phase 2 testing, bomedemstat was generally well tolerated and produced durable reductions in platelet counts, white blood cell counts, and the burden of disease-driving mutations. The phase 3 trial is comparing bomedemstat against the current best available therapy in patients who didn’t respond well to standard treatment.