TET1 (Tet Methylcytosine Dioxygenase 1)

Superior survival was also observed in high-risk patients with hypoxic tumors that had high MES/hypoxia scores in the validation cohort (GSE73517; n = 28; 3-year OS 78% vs. 26%, p = 0.0012). Our results suggest that hypoxia changes expression of genes in ADRN cells towards MES cells.

Using both clinical samples and experimental models, we demonstrate that the cell-permeable derivative dimethyl-α-ketoglutarate (DM-α-KG) exacerbates lipopolysaccharide (LPS)-induced tissue injury and cell death, whereas isocitrate dehydrogenase (IDH1) inhibition (IDH-305) or genetic ablation reduces α-KG levels and confers protection...These findings establish α-KG as a critical immunometabolic checkpoint in sepsis that licenses inflammatory cell death via TET2-mediated epigenetic control of AIM2. Our work not only elucidates a novel α-KG/TET2/AIM2 signaling axis in sepsis pathogenesis but also highlights the therapeutic potential of targeting this pathway to modulate immune responses.

In summary, our results establish TET1 as a critical promoter of HCC progression and elucidate its role in regulating the PI3K/Akt pathway. These findings highlight its value as both a prognostic biomarker and a potential therapeutic target in HCC.

Critically, co-targeting TET1/GCLC/GCH1 with low-dose ferroptosis inducers exhibits potent therapeutic effects against both ferroptosis-sensitive and -resistant AML. Our work positions TET1 as a pivotal epigenetic hub governing ferroptosis surveillance, and provides a translatable strategy to overcome ferroptosis resistance in cancer, with AML as a paradigm.

CBD exhibited strong antitumor activity in melanoma by modulating the PPARγ-TET1 complex to induce demethylation of LRSAM1, thereby suppressing tumor progression. These findings identify CBD as a promising candidate for melanoma therapy.

These findings suggest that 5hmC levels not only reflect the epigenetic state of CS tumors but also hold promise as a valuable prognostic marker for identifying patients at heightened risk of adverse outcomes. Furthermore, TET2 downregulation results in a decrease in 5hmC levels with subsequent activation of the MAPK and PI3K/Akt/mTOR pathways.

Additionally, elevated levels of pro-inflammatory cytokines IL-6, IL-27, and TNF-α were consistently observed in ALL patients, indicating heightened immune activation that may drive disease progression. Collectively, these findings underscore the pivotal role of DNA methylation in disrupting lysosomal function, leading to autophagosome accumulation and impaired recycling of cytoplasmic components.

Overexpression of either Tet1 or TRPV4 rescued the KAT6A knockdown-induced osteoclast differentiation inhibition. KAT6A promotes osteoclast differentiation through a regulatory cascade involving Tet1-mediated TRPV4 upregulation, which identifying KAT6A as a potential therapeutic target for osteoporosis treatment.

We hypothesized that thymine DNA glycosylases (TDGs) may be involved in anticancer drug resistance given their dual function of DNA repair and demethylation as well as investigated their possible involvement in the induction of β-catenin in SNUC5 cells resistant to 5-fluorouracil (SNUC5/5-FUR) and oxaliplatin (SNUC5/OXTR). Additionally, TDG significantly interacted more with TET1 in both resistant cell types than in SNUC5 cells, enhancing binding to the same locus in the β-catenin promoter. These findings suggest that TDG may be a promising target molecule for overcoming drug resistance in colorectal cancer.

Furthermore, Bcas3 overexpression promoted mitophagy and attenuated podocyte damage under HG conditions. In conclusion, TET2-mediated m5C modification contributes to podocyte injury in DN, and targeting m5C via TET2 presents a promising therapeutic strategy for DN.

Using Tet1/2/3-deficient mice and primary human acute myeloid leukemia (AML) models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo, leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.

Lactate can upregulate the expression of SGK1 through demethylation mediated by TET2, enhancing the immunosuppressive function of MDSCs to promote tumor progression. It provides the effective therapeutic targets for anti-tumor therapy.