LDHB (L-lactate dehydrogenase B chain)

Lactate induces YBX1 nuclear translocation, which in turn activates LDHB transcription. Collectively, our findings demonstrate the oncogenic roles of YBX1 and LDHB in ICC progression, identify lactate as a key energy source sustaining the activity of TCA cycle and oxidative phosphorylation, and highlight the YBX1-LDHB axis as a potential therapeutic target.

In the in vivo orthotopic xenograft osimertinib-resistant models, targeted suppression of the tumor-derived lactate/ENO1 lactylation feedback loop effectively ameliorated resistance to osimertinib. Collectively, our findings provide the basis for targeting lactate/lactate-associated signaling to combat resistance to osimertinib.

Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis.

The glycolysis-CCNB2-H3K18la-TTK/BUB1B signaling axis exacerbates the malignant progression of PDAC, providing insights into potential lactylation-based therapeutic strategies for this disease.

This study identifies m6A-related SNPs as important regulatory factors shared between OC and EM. By integrating genetic, transcriptomic, and functional data, we highlight immune and metabolic pathways-especially those involving LDHB, IFITM2, and HLA-DQB1-as key contributors to cisplatin resistance. These findings provide potential therapeutic targets and a framework for understanding m6A-associated mechanisms in ovarian cancer progression. Further in vivo studies are needed to validate the direct effects of specific m6A-SNPs.

The levels of β‑catenin mRNA and H3K18 lactylation were also found to be elevated in IH tissues. Taken together, the results of the present study revealed that lncRNA NEAT1, which is upregulated in hemangioma, binds with and stabilizes LDHB, subsequently elevates the levels of cellular lactate and H3K18 lactylation, potentiates β‑catenin transcription and ultimately enhances the proliferation of hemangioma cells.

In addition, we conducted pathway enrichment analyses to elucidate the mechanisms underlying drug resistance for paclitaxel, 5-fluorouracil (5-FU), gemcitabine, and cetuximab. Importantly, our findings are consistent with prior experimental studies, providing literature-based validation of our results. Overall, our DNN-based TL approach achieved strong predictive performance across PDX & TCGA datasets and enrichment analyses provided valuable biological insights into drug resistance mechanisms.

Furthermore, reported LDH allosteric inhibitors, including cGmC9 and fluoxetine, preferentially inhibited LDHBtr compared to the native LDHB, by preventing tetramer formation. Overall, this work highlights the central role of tetramerization in regulating LDH activity, and the therapeutic potential of targeting this process. It also establishes LDHBtr as a valuable tool for screening tetramerization disruptors, paving the way for next-generation LDH inhibitors to target cancer metabolism.

This study provides the first comprehensive inhibition profile of R. crenulata targeting LDH isoenzymes. It underscores the potential of R. crenulata in LDH-targeted therapeutics and supports its further development for cancer treatment.

This model not only advances our understanding of cancer metabolism but also suggests novel strategies for biomarker development, metabolic imaging, and targeted therapies. By reframing lactate as a central determinant of oncologic remodeling, the CILLO hypothesis provides a foundation for translational advances in oncology and personalized medicine.

We also introduced ArGO-LDHA-1, a covalent inhibitor targeting LDHA's hyperreactive arginine residues, showing potential to enhance chemotherapy efficacy. This work highlights the biological significance of arginine residues and provides a platform for large-scale profiling of arginine reactivity.

Integrated analysis of differentially expressed genes (DEGs) and differentially abundant metabolites (DAMs) demonstrated that MPA significantly alters the metabolism of key compounds (GMP, phenol, glutathione, NAD+, cytosine) and regulates critical genes (tyrosine, LDHA, LDHB). Notably, the dysregulation of genes and metabolites associated with reactive oxygen species (ROS)-related pathways may serve as a central mechanism by which MPA facilitates ferroptosis and apoptosis in bladder cancer.