Disulfidptosis

1.1 Mechanism Overview

Disulfidptosis, a newly identified type of cell death, has attracted growing attention. Although its regulatory mechanisms have not been fully elucidated, current studies indicate that upregulation of SLC7A11 serves as a key trigger for disulfidptosis. As a transporter protein, SLC7A11 mediates the cellular uptake of extracellular cystine. Under glucose deprivation, elevated SLC7A11 leads to massive intracellular cystine accumulation, which induces disulfide stress and ultimately causes cell death. Accumulating evidence suggests that disulfidptosis plays vital roles in the initiation and progression of numerous diseases. It is closely linked to tumors, neurodegenerative disorders, cardiovascular diseases and liver diseases, and is also associated with many other illnesses. Accordingly, systematic research on disulfidptosis mechanisms bears prominent clinical significance. It not only helps uncover fundamental biological principles, but also offers novel strategies for disease prevention and treatment.

Disulfidptosis Model Diagram. Glucose deprivation induces NADPH depletion. In cells with high SLC7A11 expression, this triggers cystine accumulation and aberrant disulfide bond formation, provokes actin cytoskeleton collapse, and ultimately initiates disulfidptosis.

1.2 Target List

Mechanism Module	Target (Gene/Protein)	Full Name	Function	Role in Disulfidptosis
Cystine Uptake and Transport System	SLC7A11 (xCT)	Solute carrier family 7 member 11	Cystine/glutamate antiporter that mediates cystine uptake	Core determinant of disulfidptosis; high SLC7A11 expression promotes excessive cystine import and serves as an essential prerequisite for disulfidptosis
	SLC3A2 (4F2hc)	Solute carrier family 3 member 2	Chaperone subunit of System Xc⁻	Forms the System Xc⁻ complex with SLC7A11 to facilitate cystine transport
Glucose Metabolism and NADPH Generation	Glucose	Glucose	Primary cellular carbon source	Glucose deprivation reduces cellular reducing capacity and triggers disulfidptosis
	PPP Pathway	Pentose phosphate pathway	Generates NADPH to maintain cellular reductive capacity	Provides NADPH to sustain intracellular redox balance and protect against disulfide stress
	G6PD	Glucose‑6‑phosphate dehydrogenase	Rate‑limiting enzyme of the pentose phosphate pathway	Controls PPP flux and NADPH production, influencing cellular sensitivity to disulfidptosis
	PGD	6‑Phosphogluconate dehydrogenase	Key enzyme involved in PPP‑mediated NADPH synthesis	Contributes to NADPH generation and maintenance of cellular antioxidant capacity
Cellular Redox Homeostasis	NADPH	Nicotinamide adenine dinucleotide phosphate	Major source of cellular reducing power	NADPH depletion drives thiol oxidation and aberrant disulfide bond formation, serving as a critical trigger of disulfidptosis
	GSH	Glutathione	Major intracellular antioxidant maintaining thiol reduction state	Maintains protein thiols in a reduced state and buffers disulfide stress
	GCLC/GCLM	Glutamate‑cysteine ligase catalytic subunit / modifier subunit	Rate‑limiting enzyme complex for glutathione biosynthesis	Regulates GSH synthesis and determines cellular antioxidant capacity
	TXN	Thioredoxin	Component of the thioredoxin redox system	Mediates disulfide bond reduction and maintains protein thiol homeostasis
Disulfide Bond Accumulation and Protein Crosslinking	Cystine	Cystine	Oxidized dimer of cysteine containing a disulfide bond	Accumulates after SLC7A11‑mediated import and increases intracellular disulfide burden
	Cysteine	Cysteine	Reduced form of cystine and precursor for GSH synthesis	Normally utilized for glutathione synthesis after cystine reduction
	Protein disulfide bonds (S–S)	Protein disulfide bonds	Covalent bonds formed between cysteine residues	Aberrant accumulation induces protein crosslinking, protein dysfunction, and proteotoxic stress
Cytoskeletal Collapse and Actin Remodeling	ACTB (β‑actin)	Actin beta	Major cytoskeletal actin isoform	Primary execution target of disulfidptosis; abnormal disulfide crosslinking disrupts cytoskeletal integrity
	ACTG1 (γ‑actin)	Actin gamma 1	Actin isoform involved in F‑actin network organization and stabilization	Maintains F‑actin network stability and cytoskeletal structure
	F‑actin	Filamentous actin	Polymerized actin cytoskeletal structure	Undergoes contraction, aggregation, and collapse, representing the major morphological hallmark of disulfidptosis
	PFN1	Profilin 1	Regulates actin polymerization dynamics	Modulates actin filament assembly and remodeling
	FLNA	Filamin A	Cytoskeletal crosslinking protein	Maintains cytoskeletal connectivity and mechanical stability

1.3 Application Scheme

Purpose	Markers/Assays
Target verification	SLC7A11
Metabolic stress evaluation	NADPH/NADP⁺
Disulfide stress detection	Protein‑S‑S
Phenotypic identification	ACTB + F‑actin
Cell death confirmation	PI / LDH
Exclusion of ferroptosis	GPX4 + Ferrostatin‑1

1.4 References

1. Liu X, Nie L, Zhang Y, et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis[J]. Nature Cell Biology, 2023, 25(3): 404‑414. DOI: 10.1038/s41556‑023‑01091‑2.
2. Zheng T, Li X, Chen Y, et al. Disulfidptosis: A new form of programmed cell death[J]. Journal of Experimental & Clinical Cancer Research, 2023, 42: 137.
3. Machesky LM. Deadly actin collapse by disulfidptosis[J]. Nature Cell Biology, 2023, 25: 353‑354.
4. Koppula P, Zhuang L.Disulfidptosis: Disulfide stress‑induced cell death[J]. Trends in Cancer, 2023, 9(10): 857‑860.