Copper homeostasis imbalance and cuproptosis: Emerging targets and strategies for gastrointestinal tumor therapy

Table 1 Key cuproptosis regulators in gastrointestinal tumors

Regulator	Main role in cuproptosis	Relevance in gastrointestinal tumors	Evidence level	Ref.
SLC31A1/CTR1	Mediates copper influx and contributes to intracellular copper accumulation	Associated with copper and platinum drug uptake; altered expression may affect therapeutic response in digestive tumors	Clinical association + preclinical evidence	[29,68]
ATP7A/ATP7B	Copper efflux transporters that reduce intracellular copper accumulation	Upregulation is associated with platinum resistance and altered copper homeostasis in GC, CRC, and esophageal cancer	Clinical association + functional studies	[66,67,69-74]
ATOX1	Copper chaperone involved in copper transport and transcriptional regulation	Supports tumor proliferation and copper-dependent signaling in gastrointestinal malignancies	Preclinical + clinical association	[29,32,34]
FDX1	Reduces Cu2+ to Cu+ and supports LIAS-dependent protein lipoylation	Frequently downregulated in GC/CRC; low expression is associated with poor prognosis and reduced cuproptosis sensitivity	Bioinformatic cohorts + mechanistic studies	[44,87-93]
LIAS	Catalyzes lipoic acid biosynthesis required for mitochondrial protein lipoylation	LIAS regulation affects cellular sensitivity to elesclomol and copper-induced cuproptosis	Preclinical mechanistic evidence	[44,121,123]
DLAT	Lipoylated TCA-cycle protein and key substrate for copper-induced aggregation	DLAT abundance may influence mitochondrial metabolism, prognosis, immune features, and response to cuproptosis induction	Preclinical + clinical association	[42,43,94,235,236]
MTF1/FTH1/ISCA2	Regulates metal stress, iron storage, and Fe-S cluster homeostasis	May suppress both ferroptosis and cuproptosis sensitivity in GC by promoting iron storage and Fe-S cluster assembly	Preclinical mechanistic evidence	[106]
HIF-1α	Promotes glycolytic reprogramming and reduces mitochondrial dependence	Hypoxia/HIF-1α activation may reduce cuproptosis sensitivity by suppressing TCA-cycle activity and FDX1/DLAT expression	Preclinical evidence	[47,76,269]
CDKN2A/SNHG26/E2F3	Resistance-associated regulators of elesclomol-induced cuproptosis	Associated with resistance to cuproptosis induction in CRC models	Preclinical evidence	[125,126,240,241]
PTBP3/COX11 axis	Alters mitochondrial copper handling	PTBP3-mediated COX11 exon skipping may reduce mitochondrial copper content and contribute to cuproptosis evasion in GC	Preclinical evidence	[243]

SLC31A1: Solute carrier family 31 member 1; CTR1: Copper transporters; ATP7A: ATPase copper transporting alpha; ATP7B: ATPase copper transporting beta; GC: Gastric cancer; CRC: Colorectal cancer; ATOX1: Antioxidant 1 copper chaperone; FDX1: Ferredoxin 1; LIAS: Lipoic acid synthase; DLAT: Dihydrolipoamide S-acetyltransferase; TCA: Tricarboxylic acid cycle; MTF1: Metal regulatory transcription factor 1; FTH1: Ferritin heavy chain 1; ISCA2: Iron-sulfur cluster assembly 2; HIF-1α: Hypoxia-inducible factor-1α; CDKN2A: Cyclin dependent kinase inhibitor 2A; SNHG26: Small nucleolar RNA host gene 26; E2F3: E2F transcription factor 3; PTBP3: Polypyrimidine tract binding protein 3; COX11: Cytochrome c oxidase assembly factor 11.