Table 1.

Potential targets for the application of prevention and treatment of disulfide stress in cardiovascular diseases.

Type	Name	Experimental Cell Models	Mechanism of Action	Outcomes	(Ref)
Trx-1 Inhibitor	PX-12	HT-29, HUVEC, MRCV	Covalently binds to the active site cysteine residue of Trx1, leading to decreased Trx1 activity	Reduces vascular permeability, increases tumor cell apoptosis	[111]
	APMX 464	HT-29, HUVEC, MRCV	Covalently binds to the active site cysteine residue of Trx1, inhibiting Trx1 activity	Decreases tumor cell proliferation with minimal effects on resting cells	[112]
Secondary Metabolites	Puerarin	RAW264.7, ApoE−/− mouse macrophages	Activates PERK/Nrf2 pathway, upregulates Trx1 and TrxR1 expression, reduces intracellular ROS production	Reduces macrophage lipid uptake, decreases lipid deposition in atherosclerotic plaques	[113,114]
	Diallyl Trisulfide (DATS)	U87, U251, MES28, Nude mouse brain tumor model	Directly covalently binds to Trx1's Cys32 and Cys 35 residues, inhibiting Trx1 activity, leading to ROS accumulation	Enhances the cytotoxic effect of radiotherapy on glioma cells, inhibits tumor growth	[115,116]
Recombinant Trx	Recombinant Trx-1	RAW264.7 macrophages	Its active site disulfide bond reduction mechanism, scavenges ROS, inhibits p38 MAPK activation and LOX-1 expression, reducing foam cell formation and apoptosis	Significantly inhibits ox-LDL induced foam cell formation and apoptosis, upregulates Bcl-2 expression, downregulates Bax and caspase-3 expression	[123]
	HSA-Trx	AKI to CKD mice	Its fusion protein's disulfide bond reduction activity, enhances renal antioxidant capacity, inhibits inflammatory response, reduces tubular injury and fibrosis	Accelerates renal function recovery, reduces renal fibrosis, inhibits inflammatory cell infiltration, restores renal tubular cell apoptosis and cell cycle arrest	[117]
	xMPs (CB3)	Murine peritoneal macrophages	Mimics the active site Cys32-Gly-Pro-Cys 35(CXXC) of Trx-1, maintains intracellular redox balance, reduces ROS generation, and diminishes inflammation	CB3 dose-dependently reduces ROS levels in LPS-activated macrophages,	[118]
Direct Disulfide Reduction	2DG Glucose Analogue	UMRC6 cells	Provides NADPH to reduce disulfide bond accumulation	Significantly restores NADPH levels, reduces accumulation of γ-glutamylcysteine and glutathione disulfide, prevents cell death	[120]
	NAC (N-acetylcysteine)	UMRC6 cells	Supplies intracellular cysteine and promotes GSH synthesis	Restores intracellular redox system balance, reduces cell death	[121]
	Penicillamine	UMRC6 cells	Disulfide bond exchange prevents accumulation of cysteine disulfide bonds	Restores intracellular redox system balance, reduces cell death	[122]
Grx-1 Inhibitor	AAV-shGrx	C2C12 skeletal muscle cells	Inhibits Grx-1 expression, inducing disulfide stress	After 6 weeks, Grx mRNA in muscle decreased by 80 %, protein level decreased by 50 %, with localized ROS accumulation	[119]
Grx-1 Overexpression	Adenovirus Grx1	WT and ApoE−/− mice	Reduces glutathionylation of intracellular proteins, inactivates PKB/eNOS, and inhibits Rac1 degradation	Overexpression of Grx in transgenic mice attenuates collagen deposition, inhibits endothelial hypercholesterolemia	[63]