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. 2019 Oct 15;10:4681. doi: 10.1038/s41467-019-12606-7

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — Knockdown of PHGDH impaired serine biosynthesis and induced oxidative stress. a Knockdown of PHGDH impaired serine synthesis pathway (SSP), leading to accumulation of 3-phosphoglyceric acid (3-PG) and reduced production of nicotinamide adenine dinucleotide+hydrogen (NADH), α-ketoglutarate (α-KG), and serine. b Glycolytic metabolites cannot be branched into SSP upon knockdown of PHGDH, causing the accumulation of most glycolytic metabolites glucose 1-phosphate (G1P), glucose-6-phosphate (G6P), fructose 6-phosphate (F6P), fructose 1,6-bisphosphate (F1,6P), glyceraldehyde 3-phosphate (G3P), phosphoenolpyruvate (PEP), and pyruvate (gray bar: non-target control; red bar: PHGDH knockdown clones). c Knockdown of PHGDH resulted in reduced nicotinamide adenine dinucleotide phosphate (NADPH) production. d Sorafenib treatment augmented reactive oxygen species (ROS) level. Knockdown of PHGDH intensified the Sorafenib-induced oxidative stress in HCC cells (black line: non-target control treated with vehicle; light red line: non-target control treated with Sorafenib; blue line: PHGDH knockdown clones treated with vehicle; deep red line: PHGDH knockdown clones treated with Sorafenib). e H₂O₂ and tert-butyl hydroperoxide (tBHP) treatment at 20 and 200 μM for 24 h respectively induced PHGDH expression in HCC cells in both mRNA and protein level. f Knockdown of NRF2 (Nuclear factor erythroid 2-related factor 2) alleviated Sorafenib-induced PHGDH up-regulation in HCC cells in both mRNA and protein level. g Treatment of α-KG at 4 mM and NAC at 5 mM for 48 h substantially inhibited Sorafenib (5 μM) and NCT-503(40 μM)-induced apoptosis in HCC cells. The error bar represents SEM. n = 3 biologically independent samples in panels a–f and 5 in panel g. Source data are provided as a Source Data file (Student's t-test *P < 0.05, **P < 0.01, ***P < 0.001)