Fig. 2

Mechanisms of cuproptosis. The transportation of Cu²⁺ by Cu ionophores and the uptake of Cu⁺ by SLC31A1 lead to the excessive accumulation of Cu within cells. Cu ionophores, such as elesclomol, can transport Cu²⁺ into mitochondria, where Cu²⁺ is reduced to Cu⁺ by FDX1. FDX1 is a crucial regulatory protein for the lipoylation of mitochondrial TCA cycle enzymes, particularly DLAT. Accumulated Cu⁺ in mitochondria induces DLAT aggregation by directly binding to lipoylated DLAT and destabilizes Fe–S cluster proteins, ultimately triggering mitochondrial proteotoxic stress and resulting in cuproptosis. Key positive regulators of cuproptosis include LIAS, DLD, LIPT1, and FDX1 from the LA pathway, as well as DLAT, PDHA1, and PDHB from the PDH complex. Important inhibitors of cuproptosis include MTF1, GLS, and CDKN2A. FDX1 promotes G6PD degradation by binding to it, resulting in GSH reduction and intensified cuproptosis. METTL16 enhances cuproptosis by promoting FDX1 accumulation via m6A modification on FDX1 mRNA, a process inhibited by SIRT2 through delactylating METTL16 at K229. MELK increases DLAT expression through the PI3K/mTOR signaling pathway, enhancing mitochondrial function and cuproptosis. AMPK activated by elesclomol–Cu facilitates cuproptosis. Elesclomol–Cu upregulates PPP1R15A to promote proteotoxic stress by enhancing EIF2S1 and 4E-BP1-associated translation initiation, thereby enhancing cuproptosis. p32 enhances elesclomol–Cu-induced cuproptosis by promoting lipo-DLAT oligomerization. MUC20 induces cuproptosis by inhibiting CDKN2A expression. GAPDH and ARID1A inhibit cuproptosis by promoting cellular glycolysis, while SLC7A11 inhibits cuproptosis by upregulating intracellular GSH. SLC31A1, the solute carrier family 31 member 1; FDX1, ferredoxin 1; ES, elesclomol; Disulfiram, disulfiram; DLAT, dihydrolipoamide S-acetyltransferase; TCA, tricarboxylic acid; LIAS, LA synthase; LIPT1, lipoyl transferase 1; DLD, dihydrolipoamide dehydrogenase; PDHA1, pyruvate dehydrogenase E1 subunit alpha 1; PDHB, pyruvate dehydrogenase E1 subunit beta; MTF1, metal-regulatory transcription factor-1; GLS, glutaminase; CDKN2A, cyclin-dependent kinase inhibitor 2A;G6PD, glucose-6-phosphate dehydrogenease; GSH, glutathione; SIRT2, Sirtuin 2; SLC7A11, solute carrier family 7 membrane 11; MUC20, Mucin 20; MELK, maternal embryonic leucine zipper kinase; ARID1A, AT-rich interactive domain 1A; AMPK, adenosine 5 ‘-monophosphate (AMP)-activated protein kinase; TIGD1, trigger transposable element-derived 1; WASF2, Wiskott-Aldrich syndrome protein family member 2