WNK1 (WNK Lysine Deficient Protein Kinase 1)

RNA interference-mediated downregulation of LRRC8A reduces proliferation in patient-derived GBM cell cultures, suggesting that VRACs promote cancer cell growth. LRRC8A/VRAC-mediated effects on cell proliferation are driven by a mechanism involving the chloride-sensitive protein kinase WNK1, mTOR complex 2 and activation of downstream kinases AKT and SGK.

CAF exposure enhanced SIAH2 expression, CSC spheroid growth, and resistance to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, whereas SIAH2 depletion effectively abrogated these effects. Collectively, these findings identify the SIAH2/WNK1 axis as a central metabolic regulator linking glycolysis, CSC maintenance, and microenvironment-driven therapy resistance in CRC, highlighting its potential as a therapeutic target.

WNK1 competitively binds to Keap1 to facilitate NRF2 nuclear translocation, thereby activating the NRF2/GCH1/BH4 pathway and inhibiting ferroptosis in PC cells. These findings provide significant insights for further research on PC and the development of therapeutic strategies.

EPA in the presence of TMZ reduced the phosphorylation of GSK3α/β, Akt 1/2/3, HSP27, and WNK1, while DHA reduced the phosphorylation of ERK 1/2, GSK3α/β, AMPKα1, Akt 1/2/3, and WNK1, thereby leading to additive or synergistic effects of EPA or DHA in combination with TMZ. Overall, the present study highlights the alterations seen in TMZ-resistant glioma cells when exposed to EPA or DHA and demonstrates the therapeutic potential that modulation of lipid metabolism can exert upon important aspects of glioma cell biology.

WNK1 depletion phenocopies Cx43 knockdown and reduces c-MYC expression and tumor initiation. Together, these results define a signaling axis downstream of Cx43 that promotes tumor growth and cancer stem cell phenotypes in glioblastoma.

Additionally, the WNK1-AMPK pathway was, at least in part, involved in the high [K+]e-induced upregulation of CCL2. Collectively, modulating KCa3.1 and LRRC8A activities offers a promising strategy to suppress CCL2 secretion in TAMs, potentially limiting the CCL2-induced infiltration of immunosuppressive cells (TAMs, Tregs, and MDSCs) in the TME.

Moreover, our results suggest that O-GlcNAcylation affects WNK4 function in both osmolarity control and ferroptosis, with potential implications ranging from blood pressure regulation to neuronal health and survival. This work demonstrates the functional regulation of the KLHL3/WNK axis by O-GlcNAcylation and supports a broader model of O-GlcNAc serving as a general regulator of KLHL signaling and proteostasis.

Unexpectedly, the WNK1-selective inhibitor (WNK-IN-11), triggered a dramatic and rapid (within 1 h) spheroid to fibril transition of GFP-MxA condensates in live cells, but without affecting MxA antiviral function. The new data suggest a novel hypothesis for the anatomic localization of oral cancer in the U-shaped "high-risk" zone in the mouth: dysfunction of biomolecular condensates in oral cells along the beverage transit pathway through the mouth due to repetitive tonicity and temperature stresses that might underlie a prooncogenic progression.

Our results show that phosphorylation of CARMIL1 in the C-terminal domain highly influences actin cytoskeletal organization. It offers new insights on CARMIL1-mediated cellular functions, deepening our comprehension of its involvement in cytoskeletal dynamics.

A hub gene WNK1 was validated and acted as an oncogene affecting ovarian cancer cell viability and migration. These findings demonstrate that a novel CSOARG model can effectively predict the prognosis and therapeutical responses of patients with ovarian cancer, which may assist clinicians in implementing better practices.

Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression.