Fig. 2
From: Tackling cuproptosis: from metabolic rewiring to therapeutic exploitation in cancer
Regulation of cuproptosis by p53. p53 regulates cuproptosis possibly through multiple mechanisms. A recent study reveals that p53 enhances cuproptosis sensitivity in cancers via the circular RNA circFRMD4A. It binds to PKM2, blocking its tetramerization and glycolytic activity, thereby redirecting glucose flux to the TCA cycle to amplify mitochondrial respiration – a prerequisite for copper-induced toxicity. Beyond the experimentally validated circFRMD4A-PKM2 axis, p53 is proposed to regulate cuproptosis through different pathways. p53 suppresses glycolysis by inhibiting GLUTs and glycolytic enzymes (HK2, PFK1, LDHA), providing a key metabolic environment for sensitizing cuproptosis. Conversely, mutant p53 promotes glycolysis by activating HK2 and PKM2, potentially inducing cuproptosis resistance. p53 also amplifies mitochondrial oxidative capacity by upregulating GLS2, SLC1A3, SCO2, and AIFM1. Additionally, p53 modulates Fe-S cluster biogenesis via ISCU, FXN, FDXR, and HSPA9, which balances Fe-S stability and affects the lipoylation pathway. In redox regulation, p53 reduces GSH by suppressing SLC7A11 but activates TIGAR or NRF2 to mitigate copper toxicity, acting as a dual sensor to eliminate copper-overloaded cells or protect stressed cells with reversible damage
