HKDC1, short for hexokinase domain containing protein 1, is a relatively recently identified human gene that encodes a protein belonging to the hexokinase family, the group of enzymes responsible for the first step of glucose metabolism. First characterized through genomic searches in the mid-2000s, HKDC1 has since emerged as a surprisingly versatile player in human health, with connections to gestational diabetes, fatty liver disease, several cancers, and even cellular aging. What makes it especially interesting is that it was hiding in plain sight for decades, overlooked because its enzymatic activity seemed too weak to matter, until researchers began finding it at the center of processes far beyond simple sugar metabolism.
How HKDC1 Was Found
Hexokinases are among the most fundamental enzymes in biology. They attach a phosphate group to glucose, trapping it inside cells so it can be burned for energy. For years, scientists recognized four human hexokinases (HK1 through HK4, the last also known as glucokinase). In 2008, a comparative genomics study identified a fifth hexokinase-like gene conserved across diverse vertebrate species, from fish to mammals. The researchers noted that HKDC1 retained the amino acid residues responsible for hexokinase activity, suggesting it was likely a functional enzyme rather than a leftover evolutionary relic.1Comparative Biochemistry and Physiology Part D: Genomics and Proteomics. Molecular evolution of the vertebrate hexokinase gene family: Identification of a conserved fifth vertebrate hexokinase gene Evolutionary analysis later clarified that HKDC1 arose from a gene duplication of HK1, with which it shares about 71 percent sequence similarity.2PubMed Central. Phylogenetic investigation of the 100 kDa hexokinase enzyme family with the topiary ancestral sequence reconstruction pipeline
Despite this conservation, HKDC1 initially puzzled researchers because it did not behave the way they expected a hexokinase to behave. Its enzymatic activity appeared far weaker than the other four hexokinases in standard lab assays, prompting debate over whether it was truly a hexokinase at all or something else entirely wearing a hexokinase-shaped coat.3PubMed Central. Studies on the Tissue Localization of HKDC1, a Putative Novel Fifth Hexokinase, in Humans
A Hexokinase With Unusual Properties
The question of whether HKDC1 is truly a hexokinase has produced conflicting results, and the disagreement itself is revealing. One recent biochemical characterization found that purified human HKDC1 is actually a robust hexokinase, but with a unique affinity for glucose. Its glucose affinity sits at about 0.49 mM, which is distinctly different from all four other human hexokinases. Like HK1, the catalytic action resides in the C-terminal half of the protein, while the N-terminal domain appears inactive.4PubMed Central. Characterization and Inhibition of Human Hexokinase Domain Containing Protein 1 Reveals an Enzyme with Unique Catalytic and Regulatory Traits
Other labs, however, have reported much lower activity. When one group purified recombinant HKDC1 alongside HK1 and glucokinase, HKDC1 showed such low-affinity activity that they could not even properly calculate its kinetic parameters under standard conditions. Even after testing different concentrations of ATP and magnesium, or separating the N-terminal and C-terminal halves, the activity remained stubbornly modest. In cells engineered to express HKDC1 with minimal background from other hexokinases, the protein produced only a small bump in total hexokinase activity.5Endocrinology. Hepatic HKDC1 Expression Contributes to Liver Metabolism
This discrepancy may reflect differences in experimental methods, protein preparation, or the possibility that HKDC1 needs specific partners or post-translational modifications present in living cells to reach full activity. Whatever the explanation, the pattern that has become clear is that HKDC1’s importance in health extends well beyond how fast it can phosphorylate glucose in a test tube. Its most consequential roles seem to involve mitochondria, cellular stress responses, and metabolic regulation at a systems level.
The Pregnancy Connection
HKDC1 first attracted widespread medical interest not through enzymology but through genetics. A large, multi-ethnic genome-wide association study looking at blood sugar traits during pregnancy flagged the HKDC1 locus as one of only two novel genetic regions linked specifically to glucose handling in pregnant women, with no equivalent association in the general population.6PubMed Central. Genetic Studies of Gestational Diabetes and Glucose Metabolism in Pregnancy The second locus was near a gene called BACE2. Together, these findings suggested that pregnancy engages metabolic pathways that are mostly dormant or unimportant outside of gestation.7PubMed. Genetics of Gestational Diabetes Mellitus and Maternal Metabolism
Follow-up studies in mice explored what HKDC1 actually does in the liver during pregnancy, and the results were striking. When researchers boosted HKDC1 expression in mouse livers during late gestation, the animals showed improved glucose tolerance and better insulin sensitivity, essentially reversing the insulin resistance that naturally peaks in late pregnancy. Conversely, knocking HKDC1 out of the liver during pregnancy significantly impaired glucose tolerance. The overexpressing mice also showed reduced production of new glucose by the liver and shifted their energy use toward burning fat and producing ketone bodies, suggesting HKDC1 helps the pregnant body redistribute fuel, sparing glucose for the growing fetus while the mother relies more on fat.8PubMed Central. Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice At the molecular level, enhanced HKDC1 expression during pregnancy was associated with better activation of a key insulin-signaling protein called Akt, along with higher levels of circulating fatty acids and ketones during fasting.9PubMed Central. The Role of Hexokinase Domain Containing Protein-1 in Glucose Regulation During Pregnancy
These findings position HKDC1 as a metabolic switch that helps fine-tune how the body handles fuel during the unique demands of pregnancy. When the switch works properly, glucose, fat, and ketone metabolism are balanced. When it fails, the mother may develop the kind of glucose intolerance that underlies gestational diabetes.
Fatty Liver Disease
Outside of pregnancy, HKDC1 expression in the liver is normally very low. It ramps up, however, under metabolic stress. Researchers found that HKDC1 levels were elevated in liver tissue from patients with more advanced stages of nonalcoholic fatty liver disease, and similarly in mice fed diets that caused liver inflammation and scarring. The same study observed that overexpressing HKDC1 in liver cells led to defective mitochondrial function and altered cellular metabolism, raising the possibility that HKDC1 induction in liver disease is not merely a bystander response but may actively contribute to disease progression.5Endocrinology. Hepatic HKDC1 Expression Contributes to Liver Metabolism
A more recent study tested this directly. In a mouse model of metabolic dysfunction-associated steatohepatitis (the updated name for what was previously called nonalcoholic steatohepatitis, or NASH), deleting HKDC1 specifically from the liver protected mice against obesity, glucose intolerance, and the hallmarks of liver disease, including fat accumulation, inflammation, and fibrosis. The same study confirmed that HKDC1 protein was elevated in obese women diagnosed with the condition and that its levels correlated with the severity of liver damage.10PubMed. Hepatic HKDC1 deletion alleviates western diet-induced MASH in mice
This creates an interesting duality. During pregnancy, higher liver HKDC1 appears helpful, improving glucose disposal and insulin sensitivity. In the context of chronic metabolic disease and obesity, higher liver HKDC1 seems harmful, promoting fat deposition and inflammation. Whether this reflects a time-limited adaptation going wrong, a dose effect, or context-dependent interactions with different signaling environments remains an open question.
Cancer and Metabolic Reprogramming
HKDC1 has quickly become a molecule of interest in cancer biology. A pan-cancer analysis drawing on large genomic databases found that HKDC1 expression is significantly elevated across a wide range of tumor types, including bladder, breast, bile duct, and stomach cancers, compared with normal tissue.11PeerJ. A comprehensive prognostic and immunological analysis of hexokinase domain containing protein-1 (HKDC1) in pan-cancer A review of the field identified HKDC1 as particularly important in lung, liver, colorectal, and gastric cancers, where its upregulation correlates with worse clinical outcomes and contributes to tumor progression through enhanced glycolysis and immune evasion.12PubMed Central. HKDC1 in Cancer: Mechanisms, Clinical Applications, and Future
Cancer cells are famously reliant on glycolysis, even when oxygen is plentiful, a phenomenon known as the Warburg effect. HKDC1 fits neatly into this metabolic rewiring. In gastric cancer, for example, experimental work showed that overexpressing HKDC1 promoted glycolysis, cell proliferation, and tumor growth. Perhaps more worryingly, high HKDC1 also conferred resistance to three common chemotherapy drugs: cisplatin, oxaliplatin, and 5-fluorouracil. The resistance mechanism involved activation of DNA damage repair pathways fed through NF-κB signaling.13PubMed Central. HKDC1 upregulation promotes glycolysis and disease progression, and confers chemoresistance onto gastric cancer
In liver cancer specifically, HKDC1 interacts directly with mitochondria and appears necessary for optimal mitochondrial function in tumor cells. Knocking out HKDC1 in liver cancer cell lines dramatically reduced both baseline and maximum rates of mitochondrial respiration, lowered ATP levels, and caused mitochondrial structural abnormalities including higher calcium levels and increased production of damaging reactive oxygen species.14PubMed Central. The hexokinase “HKDC1” interaction with the mitochondria is essential for liver cancer progression Clinically, patients with hepatocellular carcinoma whose tumors expressed high levels of HKDC1 had shorter survival times, and elevated HKDC1 was associated with more tumors and larger tumor size. Recent work has also linked HKDC1 to resistance against lenvatinib, one of the frontline drugs for advanced liver cancer, through metabolic reprogramming of polyamine pathways and immune escape.15Clinical and Molecular Hepatology. HKDC1-mediated polyamine rewiring drives lenvatinib resistance and immune escape in hepatocellular carcinoma
Epigenetic Control of HKDC1 in Tumors
One reason HKDC1 may be so consistently overexpressed in cancers is epigenetic deregulation, changes to how the gene is read rather than changes to the gene’s DNA sequence itself. In colorectal cancer, HKDC1 was identified as the only glycolysis-pathway gene that was hypomethylated (meaning the chemical tags that normally keep it quiet were removed) consistently across multiple independent datasets. When researchers compared this methylation pattern to actual gene activity, the correlation was clear: less methylation meant more HKDC1 protein.16PubMed Central. Epigenetic reprogramming of hexokinase domain containing 1 (HKDC1) promotes proliferation in colorectal cancer
MicroRNAs offer another layer of regulation. In endometrial cancer, researchers mapped out a signaling chain in which a long non-coding RNA called HOXC-AS2 suppresses a microRNA (miR-876-5p) that would otherwise keep HKDC1 levels in check. In high-glucose conditions, this regulatory axis shifts to allow HKDC1 overexpression, linking the metabolic environment directly to gene regulation and tumor behavior.17PubMed Central. The HOXC-AS2/miR-876-5p/HKDC1 axis regulates endometrial cancer progression in a high glucose-related tumor microenvironment The high-glucose angle is notable because it suggests a mechanism by which metabolic diseases like diabetes could feed directly into cancer-promoting gene expression, though that link is still being investigated.
HKDC1 at the Mitochondria and Beyond
Much of HKDC1’s influence on health seems to flow through its physical relationship with mitochondria, the organelles that generate most of a cell’s energy. In liver cells, HKDC1 localizes largely to the outer mitochondrial membrane, where it interacts with voltage-dependent anion channels, the pores through which molecules pass in and out of mitochondria.18PubMed Central. HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence This is the same type of anchoring used by HK1 and HK2, but HKDC1 appears to have additional responsibilities that those enzymes do not share.
One of the more surprising findings is that HKDC1 is essential for maintaining contact between mitochondria and lysosomes, the cellular recycling centers. When HKDC1 was absent, cells lost the ability to efficiently clear damaged lysosomes, and the contact points between mitochondria and lysosomes fell apart. The downstream consequence was cellular senescence, the state in which cells stop dividing and begin secreting inflammatory molecules.18PubMed Central. HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence This links HKDC1 to the broader biology of aging, not just metabolic disease.
Stress Response and the ISR
HKDC1 expression is also controlled by cellular stress. When cells experience endoplasmic reticulum stress (essentially, when the protein-folding machinery gets overwhelmed) or mitochondrial respiratory chain problems, HKDC1 is substantially upregulated. This induction is part of the integrated stress response, a conserved signaling cascade that cells activate when they encounter various threats. HKDC1 appears to be regulated by ATF4, one of the master transcription factors of this pathway. Blocking the integrated stress response with a drug called ISRIB substantially reduced the stress-induced rise in HKDC1.19PLoS ONE. Implication of KRT16, FAM129A and HKDC1 genes as ATF4 regulated components of the integrated stress response
This stress-responsive nature helps explain the pattern seen across diseases. In pregnancy, the metabolic stress of supporting fetal growth may help trigger HKDC1 in the liver. In fatty liver disease, the lipotoxic stress of excess fat could do the same. In cancer, the harsh tumor microenvironment, often marked by nutrient scarcity and low oxygen, provides exactly the kind of conditions that activate integrated stress response signaling. HKDC1 may function, at least partly, as a stress-adaptation gene that cells deploy when metabolic conditions become difficult.
Aging and Neurodegeneration
The connection between HKDC1 and cellular senescence extends into brain health. Research examining HKDC1 expression across different ages and in neurodegenerative conditions found that silencing HKDC1 in brain tissue led to increased markers of both senescence (p21, p53) and neuroinflammation (TNF-alpha, COX-2, IL-1-beta).20PubMed Central. Silencing of the Metabolic Gene HKDC1 Is Associated With Aging and Neurodegeneration in Mice and Humans The implication is that HKDC1 activity in neurons may help keep senescence and inflammation in check, and that its decline with age could contribute to the neuroinflammatory environment that precedes conditions like Alzheimer’s disease.
This is still early-stage work, and it is worth noting that the direction of HKDC1’s effect appears to flip depending on the tissue. In liver cancer, more HKDC1 promotes disease. In the aging brain, less HKDC1 may promote disease. The common thread seems to be that HKDC1 helps cells manage mitochondrial health and metabolic stress; where that management breaks down, either through too much HKDC1 in the wrong context or too little in the right one, pathology follows.
Tissue Distribution in Healthy People
Early assumptions placed HKDC1 primarily in the liver, largely because its genetic association with glucose metabolism during pregnancy pointed there. But more comprehensive surveys have shown that HKDC1 is expressed across many human tissues.21PubMed Central. Hexokinase domain-containing protein-1 in metabolic diseases and beyond Overexpressing HKDC1 in mouse livers also offered a window into its effects on liver cell biology: it increased both the size of individual hepatocytes and their capacity for proliferation, hinting at growth-promoting functions that go beyond glucose metabolism.22Scientific Reports. Liver-specific overexpression of HKDC1 increases hepatocyte size and proliferative capacity
The wide tissue distribution is consistent with HKDC1’s involvement in fundamental cellular housekeeping, particularly mitochondrial maintenance and stress response, rather than a narrow metabolic function limited to one organ. It also raises the question of what HKDC1 does in tissues like the brain, gut, and kidney under normal conditions, questions that remain largely unanswered.
Could HKDC1 Become a Drug Target?
Given how consistently HKDC1 turns up in disease contexts, there is growing interest in developing therapies directed at it. In gastric cancer, researchers have proposed HKDC1 as both a diagnostic biomarker and a therapeutic target, since its expression tracks with tumor progression and its knockdown slows tumor growth in experimental models.23Annals of Clinical & Laboratory Science. HKDC1 in Gastric Cancer: A New Diagnostic, Prognostic Biomarker, and Novel Therapeutic Target In liver cancer, high HKDC1 has been linked to resistance against lenvatinib, suggesting that blocking HKDC1 might restore sensitivity to the drug in patients who stop responding to it.15Clinical and Molecular Hepatology. HKDC1-mediated polyamine rewiring drives lenvatinib resistance and immune escape in hepatocellular carcinoma And in fatty liver disease, liver-specific deletion of HKDC1 protected mice from diet-induced disease, pointing toward therapeutic strategies that reduce HKDC1 activity in the liver.10PubMed. Hepatic HKDC1 deletion alleviates western diet-induced MASH in mice
The challenge is specificity. Because HKDC1 appears beneficial in some contexts (pregnancy, brain aging) and harmful in others (liver disease, tumors), a drug that simply turns it off everywhere could trade one problem for another. Any future therapy would likely need to be tissue-targeted or disease-stage-specific. The recent biochemical characterization showing that HKDC1 has unique kinetic properties distinct from all other hexokinases is encouraging on this front, because it means a small-molecule inhibitor could potentially be designed to block HKDC1 without disrupting the other four hexokinases that cells depend on for normal glucose metabolism.4PubMed Central. Characterization and Inhibition of Human Hexokinase Domain Containing Protein 1 Reveals an Enzyme with Unique Catalytic and Regulatory Traits That work is still in its earliest stages, but it represents the kind of precision that would be needed to safely exploit this gene’s role in disease.