PDK1 (Pyruvate Dehydrogenase Kinase 1)

Consistent with this defect, heterozygous cells exhibited severe growth impairment under galactose conditions and a compensatory shift toward glycolytic metabolism. Together, these findings uncover a previously unrecognized chromatin-mitochondria regulatory axis linking MBD5 and MBD6 haploinsufficiency to mitochondrial dysfunction, providing mechanistic insight into how epigenetic dysregulation may contribute to ASD pathogenesis.

While historically considered undruggable, recent breakthroughs have seen the FDA approval of two potent KRAS G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849)...To elucidate mechanisms of acquired resistance, we generated a panel of resistant cell lines to the allele-specific KRAS inhibitors MRTX849 and MRTX1133 and observed an increased activation of the PDK1 and YAP1/TEAD signaling pathways...Furthermore, overexpression studies revealed that forced expression of either PDK1 or YAP1 led to increased resistance to KRAS inhibition in the sensitive lines. Taken together, our findings suggest that co-targeting PDK1 or YAP1/TEAD might be a potential approach to overcoming resistance to KRAS inhibition in NSCLC.

Molecular docking highlighted Monomethyl lithospermate as a key active component. Overall, SLC influences oxidative phosphorylation via the PDK1/PDHA1 and SIRT1/PGC-1α/NRF1/TFAM signaling pathways and downregulates the HER2 pathway, thereby ultimately inhibiting HER2-positive breast cancer progression.

This study identifies ALDH18A1, CALU, DERL1, and SUCLG2 as potential biomarkers for KIRC diagnosis and prognosis. Our findings suggest that these hub genes are involved in the dysregulation of key metabolic pathways, including the citrate cycle, and may serve as therapeutic targets in KIRC.

Similar signatures in RasV12, scrib tumors indicate that tumors co-opt these pathways to sustain growth under insulin restriction. This physiological program thus integrates systemic nutrient mobilization and local metabolic reprogramming, with implications for tissue repair but also pathologies, such as chronic wounds and cancer.

Moreover, PDK1 inhibition increased the therapeutic effect of APR-246 on TP53 mutant breast cancer in xenograft tumors. Our results suggested that intervention of PDK1 could potentially emerge as a new therapeutic strategy to impede the progression of TP53 mutant breast cancer.

In this study, 20 new derivatives were designed and synthesized through further structural optimization of the dichloroacetate (DCA) derivatives, and their inhibitory effects on PDK1 and anticancer activities were systematically evaluated...Importantly, low-dose D16 (20 mg/kg) robustly inhibited tumor growth in vivo without systemic toxicity. These findings establish D16 as a potent PDK1 inhibitor that shifts tumor metabolism, offering a promising therapeutic approach for cancer treatment.

Notably, the expression levels of these genes were found to be positively correlated, with patients exhibiting high levels of these genes tending to have poorer prognoses. These findings demonstrate that ATAD2 plays a pivotal role in the malignant progression of glioma and synergizes with E2F1 to promote PDK1 expression, suggesting its potential as a therapeutic target for glioma.

Notably, TALDO1 deacetylation inhibited its nuclear translocation and interaction with BRCA1, thereby reducing the inhibition of c-Myc transcriptional activation, promoting the expression of HK2/LDHA/PDK1, and further enhancing glycolysis independent of TALDO1 enzyme activity. This research elucidated the regulatory mechanism of TALDO1 from the perspective of acetylation modification, clarified the moonlighting functions of TALDO1 in metabolic reprogramming, and provided novel biomarkers and intervention strategies, such as HDAC inhibitors, for the clinical treatment of NPC.

The findings suggest PDK1 as a critical regulator of glycolytic metabolism and a potential therapeutic target in osteosarcoma. Targeting PDK1 could provide a novel therapeutic strategy for treating osteosarcoma and possibly other cancers.

Mechanistically, AA-induced cell death involved ROS generation, lipid peroxidation, cell cycle arrest, ferroptosis, apoptosis, and downregulation of pyruvate dehydrogenase kinase 1 (PDHK1). These findings further support the potential of AA as a selective anticancer agent and highlight the importance of assay choice in evaluating its therapeutic efficacy.

Moreover, we found that YBX1, in conjunction with PDH activation, promotes epithelial cell senescence and suppresses cancer cell proliferation. These findings indicate that PDH activation imposes a constraint on the tumorigenic potential of YBX1.