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Figure 1 2.1 Physical microenvironment 2.1.1 Hypoxia As early as 1955, hypoxia was recognized as an important marker of solid tumor TME (26)

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GSH production is supported by NRF2 through controlling several enzymes responsible for GSH synthesis, such as the glutamate-cysteine ligase (GCL) complex composed of two subunits, the modifier (GCLM) subunit and the catalytic (GCLC) subunit, which catalyze the rate-limiting step of GSH synthesis that converts cysteine and glutamate into GSH [22]