Table 1.

Ferroptosis-sensitive phenotypic features of drug-resistant cancers.

Phenotypic category	Specific characteristics	Mechanistic basis	Representative examples	References
Metabolic Reprogramming	Enhanced glutaminolysis	ASCT2/GLS upregulation → glutamate/α-KG accumulation → mitochondrial ROS → Fenton reaction	TNBC, lung cancer (↑ROS by 2–3 folds)	(62, 63)
	Lipidome remodeling (high PUFA-PLs)	ACSL4/LPCAT3 activation → AA/AdA incorporation into membranes → lipid peroxidation substrate enrichment	TNBC (ACSL4 ↑2.8-fold vs. sensitive tumors)	(64, 65)
	Iron homeostasis imbalance	NCOA4-mediated ferritinophagy + TfR1 upregulation → labile iron pool (LIP) expansion	HCC, colorectal cancer (LIP ↑40%)	(66, 67)
Antioxidant System Defects	System Xc- dysfunction (SLC7A11 downregulation)	Reduced cystine uptake → GSH depletion → GPX4 inactivation → lipid peroxide accumulation	NSCLC, ovarian cancer (GSH ↓50%)	(68, 69)
	GPX4 inhibition/downregulation	HIF-2α-mediated transcription suppression; RSL3-induced covalent modification of Sec residue	Clear cell RCC (GPX4 ↓60% under hypoxia)	(70, 71)
TME Adaptive Alterations	Hypoxic microenvironment	HIF-1α/HIF-2α → FASN/HILPDA upregulation → LD/PUFA-PL accumulation; NCOA4-mediated ferritinophagy	Solid tumors (lipid substrates ↑30% under hypoxia)	(72, 73)
	Reduced cell-cell contact (E-cadherin loss)	YAP/TAZ nuclear translocation → SLC7A11/GPX4 upregulation; FAK-PI3K-AKT → PUFA synthesis	Gastric cancer, breast cancer (EMT ↑70%)	(74, 75)