In mammalian cells, there are three isoforms of malic enzymes (MEs): a cytosolic nicotinamide adenine dinucleotide phosphate+ (NADP+)-dependent isoform (ME1), a mitochondrial NAD(P)+-dependent isoform (ME2), and a mitochondrial NADP+-dependent isoform (ME3), of which ME1 and ME2 are the major isoforms. As essential modulators of metabolism and aging, MEs have been reported to be targets for wild-type p53 (wtp53), which can transcriptionally repress their expression. Reciprocally, downregulation of ME1 and ME2 leads to wtp53 activation via distinct mechanisms (Jiang et al., 2013; Figure 1A). The TP53 gene is the most frequently mutated gene in tumors, with more than half of human cancers carrying mutations in this gene (Vogelstein et al., 2000). Compared with wtp53, the protein stability of mutant p53 (mutp53) is much higher in many tumor cells, and high levels of mutp53 usually acquire an increased oncogenic capacity. Thus, it is crucial to determine the mechanisms by which mutp53 stabilization/degradation is regulated, helping to identify therapeutic strategies that destabilize mutp53 without altering wtp53 levels. In wtp53 cells, various posttranslational modifications, including acetylation, phosphorylation, methylation, sumoylation, and ubiquitination, interfere with its proteasome-dependent clearance, resulting in p53 protein stabilization (Levine, 2019). Mutp53 is also dependent on the proteasomal pathway for degradation, and in many types of tumor cells, the accumulation of mutp53 is largely attributed to the escape from the proteasome pathway (Zhang et al., 2020). Recent studies have shown that mutp53 is regulated by different stress signals, including proteotoxic stress, DNA damage, oxidative stress, and nutrient limitation, contributing to the stabilization and accumulation of mutp53 (Mantovani et al., 2019). For example, the mevalonate pathway controls mutp53 levels through geranylgeranyl pyrophosphate (<