The study investigates the role of p53 in cancer cell survival and proliferation under serine starvation. Serine is rapidly utilized by cancer cells, and its deprivation triggers the serine synthesis pathway (SSP), suppressing aerobic glycolysis and increasing flux to the TCA cycle. Transient p53-p21 activation and cell cycle arrest promote cell survival by channeling depleted serine to glutathione synthesis, preserving cellular antioxidant capacity. Cells lacking p53 fail to complete the response to serine depletion, leading to oxidative stress, reduced viability, and impaired proliferation. The role of p53 in supporting cancer cell proliferation under serine starvation is validated in an in vivo model, suggesting that serine depletion may have therapeutic potential for p53-deficient tumors. The study also highlights the importance of p53 in coordinating metabolic remodeling in response to metabolic stress and the potential for serine depletion as a therapeutic strategy.The study investigates the role of p53 in cancer cell survival and proliferation under serine starvation. Serine is rapidly utilized by cancer cells, and its deprivation triggers the serine synthesis pathway (SSP), suppressing aerobic glycolysis and increasing flux to the TCA cycle. Transient p53-p21 activation and cell cycle arrest promote cell survival by channeling depleted serine to glutathione synthesis, preserving cellular antioxidant capacity. Cells lacking p53 fail to complete the response to serine depletion, leading to oxidative stress, reduced viability, and impaired proliferation. The role of p53 in supporting cancer cell proliferation under serine starvation is validated in an in vivo model, suggesting that serine depletion may have therapeutic potential for p53-deficient tumors. The study also highlights the importance of p53 in coordinating metabolic remodeling in response to metabolic stress and the potential for serine depletion as a therapeutic strategy.