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Cancer incidence and mortality rates are on the rise, with ovarian cancer being a significant concern globally. HKDC1 is identified as a crucial protein involved in cancer metabolism, particularly in lung, liver, colorectal, and gastric cancers. Its upregulation correlates with poor clinical outcomes and promotes tumor progression through various mechanisms, including enhanced glycolysis and immune evasion. The exploration of HKDC1's role in cancer offers potential for new therapeutic strategies and biomarkers in cancer treatment.

The tumor microenvironment (TME) is related to chronic inflammation and is currently identified as a risk factor for the occurrence and development of endometrial cancer (EC). Pyroptosis is a new proinflammatory form of programmed cell death that plays a critical role in the progression of multiple diseases. However, the important role of pyroptosis in high‐glucose (HG)‐related EC and the underlying molecular mechanisms remain elusive. In the present study, transcriptome high‐throughput sequencing revealed significantly higher hexokinase domain‐containing 1 (HKDC1) expression in EC patients with diabetes than in EC patients with normal glucose. Mechanistically, HKDC1 regulates HG‐induced cell pyroptosis by modulating the production of reactive oxygen species and pyroptosis‐induced cytokine release in EC. In addition, HKDC1 regulates TME formation by enhancing glycolysis, promoting a metabolic advantage in lactate‐rich environments to further accelerate EC progression. Subsequently, miR‐876‐5p was predicted to target the HKDC1 mRNA, and HOXC‐AS2 was identified to potentially inhibit the miR‐876‐5p/HKDC1 axis in regulating cell pyroptosis in HG‐related EC. Collectively, we elucidated the regulatory role of the HOXC‐AS2/miR‐876‐5p/HKDC1 signal transduction axis in EC cell pyroptosis at the molecular level, which may provide an effective therapeutic target for patients with diabetes who are diagnosed with EC. We elucidated the regulatory role of the HOXC‐AS2/miR‐876‐5p/HKDC1 signal transduction axis in endometrial cancer (EC) cell pyroptosis at the molecular level, which may provide an effective therapeutic target for patients with diabetes who are diagnosed with EC.

There is increasing evidence that hexokinase is involved in cell proliferation and migration. However, the function of the hexokinase domain containing protein‐1 (HKDC1) in gastric cancer (GC) remains unclear. Immunohistochemistry analysis and big data mining were used to evaluate the correlation between HKDC1 expression and clinical features in GC. In addition, the biological function and molecular mechanism of HKDC1 in GC were studied by in vitro and in vivo assays. Our study indicated that HKDC1 expression was upregulated in GC tissues compared with adjacent nontumor tissues. High expression of HKDC1 was associated with worse prognosis. Functional experiments demonstrated that HKDC1 upregulation promoted glycolysis, cell proliferation, and tumorigenesis. In addition, HKDC1 could enhance GC invasion and metastasis by inducing epithelial–mesenchymal transition (EMT). Abrogation of HKDC1 could effectively attenuate its oncogenic and metastatic function. Moreover, HKDC1 promoted GC proliferation and migration in vivo. HKDC1 overexpression conferred chemoresistance to cisplatin, oxaliplatin, and 5‐fluorouracil (5‐Fu) onto GC cells. Furthermore, nuclear factor kappa‐B (NF‐κB) inhibitor PS‐341 could attenuate tumorigenesis, metastasis, and drug resistance ability induced by HKDC1 overexpression in GC cells. Our results highlight a critical role of HKDC1 in promoting glycolysis, tumorigenesis, and EMT of GC cells via activating the NF‐κB pathway. In addition, HKDC1‐mediated drug resistance was associated with DNA damage repair, which further activated NF‐κB signaling. HKDC1 upregulation may be used as a potential indicator for choosing an effective chemotherapy regimen for GC patients undergoing chemotherapy. HKDC1 upregulation predicts resistance to cisplatin, oxaliplatin and 5‐FU in patients with GC. HKDC1 upregulation may be used as a potential indicator for choosing an effective chemotherapy regimen for GC patients undergoing chemotherapy.

Environmental and industrial Pb exposure poses a significant public health challenge. Acute exposure to high Pb concentrations can result in renal injury. Here, we revealed that N6-methyladenosine (m6A) RNA methylation was significantly upregulated in lead nephropathy and was mainly mediated by the methyltransferase METTL3. Functionally, METTL3 knockout in renal tubular epithelial cells or AAV9-mediated METTL3 silencing alleviated renal injury and the inflammatory response induced by lead acetate. METTL3 silencing in renal tubular epithelial cells reduced both m6A RNA methylation and inflammatory responses following lead acetate treatment. We identified hexokinase domain-containing 1 (HKDC1), known to function in the glycolytic pathway, as a direct METTL3 target. Importantly, HKDC1 was upregulated at both mRNA and protein levels after lead acetate treatment, thereby promoting renal injury and inflammation. Mechanistically, HKDC1 binds to ATPB and antagonizes the ubiquitinase Murf1, thereby leading to increased expression of ATPB and activation of the NF-κB signaling pathway, which promotes renal inflammation. We further confirmed that STM2457, an inhibitor of METTL3, protected against renal injury and inflammation induced by lead acetate. Collectively, our study demonstrated that the METTL3/HKDC1 axis is a potential target for the treatment of lead nephropathy, and STM2457 is expected to be a protective agent against renal injury caused by lead acetate.

Background Hexokinase domain component 1 (HKDC1) plays an oncogenic role in certain types of cancer, such as lymphoma, liver cancer, and breast cancer. Previous bioinformatics study revealed that HKDC1 was significantly upregulated in lung adenocarcinoma (LUAD). However, its biological functions and potential mechanism in LUAD have not been studied. Methods We performed bioinformatics analysis, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and a series of functional assays in vitro and in vivo to investigate the roles of HKDC1 in LUAD. Results We discovered that HKDC1 was highly expressed in LUAD tissues and cell lines, and the positive expression of HKDC1 was correlated with aberrant clinicopathological characteristics in LUAD patients. Furthermore, HKDC1 could serve as a prognostic predictor for LUAD patients. Overexpression of HKDC1 promoted proliferation, migration, invasion, glycolysis, EMT and tumorigenicity, whereas knockdown of HKDC1 produced the opposite functional effects. Mechanistically, HKDC1 could regulate the AMPK/mTOR signaling pathway to perform its biological function. Conclusions Our findings suggest that HKDC1 plays an oncogenic role in LUAD. Targeting this gene may provide a promising therapeutic target to delay LUAD progression.

Hexokinases (HKs) convert hexose sugars to hexose-6-phosphate, thus trapping them inside cells to meet the synthetic and energetic demands. HKs participate in various standard and altered physiological processes, including cancer, primarily through the reprogramming of cellular metabolism. Four canonical HKs have been identified with different expression patterns across tissues. HKs 1–3 play a role in glucose utilization, whereas HK 4 (glucokinase, GCK) also acts as a glucose sensor. Recently, a novel fifth HK, hexokinase domain containing 1 (HKDC1), has been identified, which plays a role in whole-body glucose utilization and insulin sensitivity. Beyond the metabolic functions, HKDC1 is differentially expressed in many forms of human cancer. This review focuses on the role of HKs, particularly HKDC1, in metabolic reprogramming and cancer progression.

Purpose of ReviewGestational diabetes mellitus (GDM) is a common pregnancy complication conferring an increased risk to the individual of developing type 2 diabetes. As such, a thorough understanding of the pathophysiology of GDM is warranted. Hexokinase domain containing protein-1 (HKDC1) is a recently discovered protein containing hexokinase activity which has been shown to be associated with glucose metabolism during pregnancy. Here, we discuss recent evidence suggesting roles for the novel HKDC1 in gestational glucose homeostasis and the development of GDM and overt diabetes.Recent FindingsGenome-wide association studies identified variants of the HKDC1 gene associated with maternal glucose metabolism. Studies modulating HKDC1 protein expression in pregnant mice demonstrate that HKDC1 has roles in whole-body glucose utilization and nutrient balance, with liver-specific HKDC1 influencing insulin sensitivity, glucose tolerance, gluconeogenesis, and ketone production.SummaryHKDC1 has important roles in maintaining maternal glucose homeostasis extending beyond traditional hexokinase functions and may serve as a potential therapeutic target.

Currently, research on the role of hexokinase domain-containing protein-1 (HKDC1) in neoplasm metabolism remains sparse. This study seeks to conduct a thorough investigation of HKDC1's potential functions across thirty-three different tumor types, utilizing data obtained from The Cancer Genome Atlas (TCGA). We conducted a thorough data extraction from the TCGA database, subsequently employing R (version 4.2.2) and its associated software packages for detailed analysis. Our investigation centered on evaluating the differential expression and prognostic significance of HKDC1, while also examining its connections to tumor heterogeneity, mutation profiles, and RNA modifications. Furthermore, we analyzed the relationship between HKDC1 expression and tumor immunity utilizing the TIMER analysis approach. A comprehensive analysis of various tumor types has revealed that HKDC1 is significantly upregulated in many malignant tumors. Importantly, patients with elevated HKDC1 levels in their tumor tissues often experience poorer prognoses. The association between HKDC1 expression, immune cell infiltration, and the existence of immune checkpoints suggests a possible connection between the tumor microenvironment and HKDC1, alongside tumor advancement. Gene set enrichment analysis (GSEA) further substantiates the idea that HKDC1 may play a role in several critical pathways and biological processes associated with neoplasm. Additionally, the overexpression of HKDC1 is influenced by promoter methylation and alterations in DNA copy number amplification. Furthermore, in vitro experiments demonstrated that silencing HKDC1 resulted in a marked reduction in the proliferation, migration, and invasion capabilities of neoplasm cells. Our initial pan-cancer analysis provided a comprehensive understanding of the oncogenic roles of HKDC1 across diverse cancer types. Moreover, HKDC1 has the potential to serve as a significant prognostic biomarker.

Four novel glucose metabolism risk loci ( 1 rs4746822, rs6517656, rs13342232 and rs998451) were identified in recent genome-wide association studies (GWAS) of Afro-Caribbean, European, Hispanic, Thai, Mexican, Latin American and Indian populations. None of the abovementioned SNPs has been reported in a Han Chinese population. To replicate the relationships between 1 rs4746822, rs6517656, rs13342232 and rs998451 with gestational diabetes mellitus (GDM) in a Han Chinese population. This was a case-control study which enrolled 334 pregnant women with GDM and 367 pregnant women with normal glucose tolerance. The linear regression and logistic regression were used to estimate the association between SNPs with the risk of GDM, HOMA-IR and fasting insulin levels. The fasting insulin concentration and HOMA-IR were log10 transformed before analysis. No significant differences in the alleles and genotypes of rs13342232, 1 rs4746822 and rs6517656 were observed between cases and controls. After adjusting the weekly BMI growth, pre-pregnancy BMI and maternal age, under the additive model, rs13342232 was associated with log fasting serum insulin (Beta=0.046, =0.016), log HOMA-IR level (Beta=0.061, =0.003) and fasting plasma glucose level (Beta=0.164, =0.011); 1 rs4746822 was associated with OGTT 2-hr plasma glucose level (Beta=0.239, =0.016); and rs6517656 was associated with log fasting serum insulin (Beta=-0.053, =0.044) and log HOMA-IR level (Beta=-0.060, =0.048). After correction for multiple testing, the associations of and 1 with glucose metabolism remained statistically significant. The A allele of rs998451 was not detected in this population. 1 rs4746822, rs6517656 and rs13342232 are associated with glucose metabolism in pregnant women of Han Chinese.