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. 2023 May 15;9:165. doi: 10.1038/s41420-023-01463-5

Fig. 5. Mitochondrial ROS is required for lactate-dependent activation of p38-SGK1 pathway.

Fig. 5

A Western blot analysis of p-p38, SGK1 and GPX4 in A549 and H1299 cells treated with lactate in the presence of MCT1 inhibitor α-cyano-4-hydroxycinnamate (CHC). B Western blot analysis of indicated proteins in A549 and H1299 cells stimulated with glucose in the presence and absence of MCT1 inhibitor CHC. C After transfection with LDHB siRNA for 48 h, A549 and H1299 cells were treated with different doses of glucose for 3 h. Western blot was carried out for analysis of p-p38 and GPX4 levels. D After transfection with LDHB siRNA for 48 h, A549 and H1299 cells were treated with lactate (0, 10, and 20 μM) for 3 h. Western blot was carried out for analysis of GPX4 levels. E Western blotting shows expression levels after treatment with N-acetyl- l -cysteine (NAC) in the presence of 10 mM lactate. F 48 h after transfection with different doses of superoxide dismutase 2 (SOD2) expression plasmid, H1299 cells were transfected with 20 mM lactate for 3 h. Protein levels were prepared and analyzed by western blot with antibodies against indicated proteins. G 48 h after transfection with different concentrations of mitochondrial targeted catalase (MCAT) plasmid, H1299 cells were transfected with 20 mM lactate for 3 h. Western blot was used to detected the indicated proteins. H The chemotherapeutic drug etoposide induces metabolic reprogramming towards glycolysis in the NSCLC cells. The secreted lactic acid activates the expression of GPX4 protein to inhibit ferroptosis via p38/SGK1/NEDD4L pathway, thus contributing to chemoresistance in NSCLC.