The Drug Target Potential of the GPX Family in Lipid Peroxidation Defense, Ferroptosis Regulation, and Organ Injury Protection

The GPX family constitutes an important enzymatic system in the regulation of cellular redox homeostasis and participates in peroxide clearance, termination of lipid peroxidation, maintenance of membrane homeostasis, and control of stress-induced injury. Different members exhibit clear functional specialization in tissue distribution, subcellular localization, and pathological roles. Among them, GPX1, GPX2, and GPX3 mainly participate in maintaining soluble peroxide homeostasis, GPX4 is the core node for phospholipid hydroperoxide clearance and ferroptosis regulation, and GPX7 and GPX8 are more closely associated with endoplasmic reticulum stress and proteostasis. Based on this family-level heterogeneity, GPX-related drug development is better suited to a stratified and scenario-oriented strategy, thereby promoting antioxidant intervention from broad-spectrum reactive oxygen species scavenging toward precise regulation of lipid peroxidation and cell fate networks.

Keywords: GPX family; glutathione peroxidase; GPX4; ferroptosis; lipid peroxidation; oxidative stress; drug target; antioxidant strategy; endoplasmic reticulum stress; organ protection

I. Functional Positioning and Research Value of the GPX Family

1.1 The GPX Family Is a Key Enzymatic System for the Maintenance of Redox Homeostasis

(1) The GPX family is not merely a single peroxide-clearing toolset

The GPX family includes GPX1 through GPX8. Different members show clear differences in catalytic centers, cellular compartments, and functional boundaries. Their shared feature is participation in peroxide metabolism, but they do not possess completely identical substrate spectra or physiological tasks. Accordingly, the GPX family is better defined as a multilevel redox homeostasis control module rather than a single-function enzyme group.

(2) Functional specialization within the family determines distinct pharmacological significance

GPX1 and GPX3 are more responsible for basal antioxidant buffering, GPX2 is closely associated with gastrointestinal epithelial barrier integrity and restriction of inflammation, GPX4 is the central node of the lipid peroxidation defense line, and GPX7 and GPX8 are tightly coupled to endoplasmic reticulum protein folding and oxidative stress sensing. Therefore, the drug development value of GPXs mainly derives from isoform-specific functional differences rather than from an increase or decrease in total activity.

1.2 The GPX Family Links Metabolic Injury to Cell Fate Regulation

(1) Changes in GPX activity can directly alter the threshold for cellular injury

Accumulation of peroxides not only causes damage to DNA, proteins, and lipids, but can also further trigger inflammation, mitochondrial dysfunction, and switching among cell death programs. By terminating chain peroxidation reactions, GPXs determine whether cells maintain adaptive homeostasis or instead enter apoptosis, necrosis-like injury, or ferroptosis.

(2) Their action spectrum covers tumors, neurodegenerative diseases, and organ injury

In tumors, certain GPX family members can enhance cellular tolerance to stress and therapy; in the nervous system, cardio-renal system, and inflammatory diseases, GPXs often function as tissue-protective factors. This bidirectional property gives them clear scenario-dependent value in drug development.

1.3 GPX Research Is Shifting from “Antioxidation” to “Network Regulation”

(1) Simple exogenous free radical scavenging no longer meets the needs of intervention in complex diseases

Oxidative stress in complex diseases is not an isolated event; rather, it occurs together with lipid remodeling, changes in iron metabolism, amplification of immune responses, disruption of proteostasis, and metabolic reprogramming. Therefore, relying solely on conventional broad-spectrum antioxidants often fails to achieve stable efficacy.

(2) Strategies centered on GPXs place greater emphasis on reconstruction of endogenous defense networks

Drug development centered on GPXs is essentially an effort to remodel the GSH-dependent peroxide clearance system, the lipid peroxidation termination system, and the associated stress adaptation pathways. This concept is more consistent with the current mechanism-oriented direction of antioxidant strategy development.

II. Functional Specialization and Biological Characteristics of GPX Family Members

2.1 GPX1, GPX2, and GPX3 Mainly Mediate Soluble Peroxide Homeostasis

(1) GPX1 is a basal intracellular antioxidant node

GPX1 is widely distributed in the cytosol and mitochondria and is one of the most typical basal antioxidant enzymes, mainly catalyzing the reduction of hydrogen peroxide and small-molecule organic peroxides. Its function is to buffer the persistent background of oxidative stress and reduce the probability that cells enter an injury state.

(2) GPX2 is highly associated with epithelial barrier protection

GPX2 is mainly expressed in highly proliferative epithelial tissues such as the gastrointestinal tract and plays an important role in limiting inflammation-related oxidative injury, maintaining mucosal homeostasis, and promoting epithelial repair. Its physiological protective role coexists with pro-survival effects in tumor settings, reflecting marked stage dependence.

(3) GPX3 is the major extracellular member of the family

GPX3 is mainly secreted into the extracellular environment and the circulation and is an important component of plasma antioxidant capacity. Compared with intracellular members, GPX3 is more suitable as a fluid-based biomarker and is also more appropriate for assessing systemic oxidative burden and the degree of organ injury.

2.2 GPX4 Is the Most Pharmacologically Valuable Core Member of the GPX Family

(1) The uniqueness of GPX4 lies in its direct reduction of phospholipid hydroperoxides

Unlike other family members, which more often process soluble peroxides, GPX4 can directly clear peroxy groups on membrane phospholipids, thereby blocking chain amplification of lipid peroxidation. This feature makes GPX4 a core molecule for maintaining membrane stability and suppressing ferroptosis.

(2) GPX4 determines the survival threshold of cells under high lipid oxidative pressure

Under conditions of polyunsaturated fatty acid enrichment, increased iron burden, or reduced antioxidant reserves, cellular dependence on GPX4 increases significantly. Therefore, GPX4 is both an important target for tissue protection and a key breakthrough point for ferroptosis induction in tumors.

2.3 GPX5, GPX6, GPX7, and GPX8 Illustrate the Functional Extension of the Family

(1) Research on GPX5 and GPX6 is more tissue-restricted

GPX5 is mainly associated with oxidative protection in the reproductive system, whereas GPX6 remains relatively limited in terms of tissue distribution and functional study. Their direct value in drug development is not yet as clear as that of GPX4 or GPX3, but they still hold potential significance in reproductive biology and tissue-specific injury research.

(2) GPX7 and GPX8 extend the GPX family into endoplasmic reticulum homeostasis regulation

GPX7 and GPX8 are mainly localized in ER-related compartments and participate in oxidative folding, protein processing, and stress buffering. Compared with classical GSH-dependent peroxidases, they are more suitable as regulatory nodes in diseases associated with proteostasis and ER stress.

Table 1. Functional Positioning of Major GPX Family Members

Member	Main Localization	Main Function	Drug Development Focus
GPX1	Cytosol, mitochondria	Clearance of hydrogen peroxide and small-molecule peroxides	Basal antioxidant protection, adaptation to metabolic stress
GPX2	Gastrointestinal epithelium, etc.	Mucosal barrier protection, inflammation restriction	Mucosal injury protection, stage-dependent tumor regulation
GPX3	Extracellular space, plasma	Circulating antioxidant buffering	Biomarker, organ protection
GPX4	Cytosol, mitochondria, membrane systems	Clearance of phospholipid hydroperoxides, inhibition of ferroptosis	Ferroptosis regulation, bidirectional development for tumors and tissue protection
GPX5	Reproduction-related tissues	Local oxidative protection	Reproductive system research
GPX6	Tissue-restricted	Functional studies relatively limited	Exploration in specific scenarios
GPX7	Endoplasmic reticulum	Oxidative folding and proteostasis	ER stress-related diseases
GPX8	ER membrane-associated	Protein processing, stress buffering	Inflammation, tumor reprogramming, proteostasis regulation

III. Drug Target Potential of the GPX Family

3.1 GPX4 Is the Core Target in Ferroptosis Pharmacology

(1) GPX4 inhibition can serve as a strategy for exploiting tumor vulnerability

Certain tumor cells show a marked dependence on GPX4 under conditions of high metabolism, high ROS, and extensive lipid remodeling. Once GPX4 function declines, phospholipid hydroperoxides rapidly accumulate, and cells are more likely to enter ferroptosis. Therefore, GPX4 inhibition has become an important direction for exploiting tumor vulnerabilities.

(2) GPX4-protective strategies are applicable to non-tumor injury-related diseases

In neurodegenerative diseases, ischemia-reperfusion injury, acute kidney injury, and myocardial injury, maintenance of GPX4 activity helps protect membrane structure and cell viability. Thus, the drug value of GPX4 is not unidirectional inhibition; instead, it depends on whether the disease objective is to induce death or to block injury.

3.2 GPX1 and GPX2 Are More Suitable for Scenario-Stratified Development

(1) In normal tissues, GPX1/2 are more appropriately regarded as protective targets

GPX1 and GPX2 help control persistent peroxide stress and maintain epithelial and parenchymal cell homeostasis. Especially under conditions of inflammation, mucosal injury, and elevated metabolic stress, maintenance of these enzymes is more beneficial for tissue protection.

(2) In some tumors, GPX1/2 may also become tolerance-related nodes

Tumor cells can enhance tolerance to chemotherapy, radiotherapy, and metabolic stress by increasing GPX1 or GPX2 levels. Therefore, inhibitory strategies against GPX1/2 should not be generalized systemically, but are better implemented in clearly dependent settings through patient stratification and combination therapy design.

3.3 GPX3 Possesses Dual Attributes as a Peripheral Protective Target and a Stratification Biomarker

(1) GPX3 has strong advantages for detection in body fluids

Because GPX3 exists in plasma and interstitial fluids, changes in its expression and activity can be more readily translated into blood-based detection indices. This makes GPX3 not only a peripheral antioxidant node under pathological conditions, but also useful for patient stratification and efficacy monitoring.

(2) GPX3 is more suitable for organ-protective development

In renal, pulmonary, vascular, and metabolic diseases, reduced GPX3 levels are often accompanied by aggravated oxidative stress and more severe tissue injury. Compared with the bidirectional strategic feature of GPX4, GPX3 is more strongly oriented toward protective enhancement.

3.4 GPX7 and GPX8 Represent a New Direction of Targets Related to Proteostasis

(1) GPX7/8 are not mainly characterized by classical defense against lipid peroxidation

Their biological significance is more evident in oxidative folding, protein processing, and stress buffering within the endoplasmic reticulum. This makes them key nodes linking oxidative stress to proteostasis disruption.

(2) Such targets are more suitable for homeostatic modulation than complete inhibition

Because GPX7/8 also participate in basal physiological protein processing, their pharmacological development is more suitable for moderate regulatory strategies rather than strong inhibition alone. This feature has potential value for future regulation of chronic inflammation, metabolic disease, and the tumor microenvironment.

IV. Development Pathways for Antioxidant Strategies Related to the GPX Family

4.1 Strategies for Restoring Endogenous Antioxidant Capacity

(1) Selenium supplementation and maintenance of selenoprotein synthesis are among the basic strategies

Members such as GPX1, GPX2, GPX3, and GPX4 all depend on selenium-related biosynthetic processes, and insufficient selenium supply can directly limit their function. Therefore, in settings of confirmed selenium deficiency or reduced enzyme activity, selenium supplementation can serve as a basic supportive strategy.

(2) Maintenance of GSH supply is a prerequisite for GPX function

The function of the GPX family, especially the classical GSH-dependent members, depends on glutathione supply and regeneration. Therefore, maintaining the GSH/GSSG balance, improving NADPH support, and limiting depletion of reducing power are important foundations for improving the overall efficacy of GPXs.

4.2 Network-Enhancing Antioxidant Strategies

(1) Activation of endogenous antioxidant transcriptional programs is superior to simple supplementation with free radical scavengers

Oxidative stress in complex diseases is usually accompanied by inflammation, metabolic disorder, and organelle injury, and continued protection cannot usually be achieved by relying solely on direct scavenging of ROS by exogenous small molecules. By contrast, activation of endogenous antioxidant networks is more conducive to establishing stable defense.

(2) Strategies centered on the NRF2-GSH-GPX axis are more systematic

NRF2 regulates the expression of multiple antioxidant and detoxification genes and can strengthen GPX-related defense capacity at the network level. Therefore, endogenous network activation strategies centered on NRF2 are more suitable for chronic injury and multifactorial disease settings.

4.3 GPX Mimetics and Lipid Peroxidation-Terminating Strategies

(1) GPX mimetics can serve as enzyme function replacement molecules

Certain organoselenium compounds possess GPX-like catalytic properties and can, to some extent, mimic GPX activity and help reduce peroxide burden. This idea has practical significance in scenarios in which endogenous GPX activity is reduced but direct gene manipulation is not appropriate.

(2) Lipid peroxidation chain-terminating agents are suitable for combination with GPX4-protective strategies

In ferroptosis-related injury, simply increasing general antioxidant capacity is often insufficient to block amplification of membrane lipid damage. In such cases, priority should be given to strategies that suppress the lipid peroxidation chain reaction and that are combined with GPX4 stabilization or function-restoring approaches.

4.4 Bidirectional Development Is the Core Principle of GPX Strategy Design

(1) In tissue protection settings, the focus should be on enhancing or maintaining GPX function

In neurodegeneration, acute organ injury, and inflammatory tissue destruction, the more rational intervention direction is to enhance the function of GPX4, GPX3, and related antioxidant networks, thereby reducing membrane damage and cell death.

(2) In tumors, GPX dependence can be exploited in the opposite direction

In tumors with high dependence on GPX4 or on GPX1/2, weakening their antioxidant defenses can increase sensitivity to chemotherapy, radiotherapy, and ferroptosis induction. Therefore, the key to GPX pharmacological development is not uniform enhancement or uniform inhibition, but rather precise regulation in opposite directions according to the disease objective.

V. Strategy Adaptation of the GPX Family in Different Diseases

5.1 GPX-Targeting Strategies in Tumors

(1) GPX4 is suitable for linkage with ferroptosis-inducing strategies

For tumors with high lipid peroxidation burden and marked therapeutic tolerance, combined strategies involving GPX4 inhibition, GSH depletion, or blockade of parallel defense lines can be designed to increase ferroptosis sensitivity.

(2) GPX1/2 are more suitable as auxiliary targets of stress adaptation

When tumors exhibit typical ROS tolerance or metabolic reprogramming features, GPX1/2 can be used as auxiliary targets to enhance therapeutic vulnerability, but excessive oxidative injury to normal tissues must be carefully avoided.

5.2 GPX-Enhancing Strategies in the Nervous System and Ischemia-Reperfusion Injury

(1) Maintenance of GPX4 can limit membrane lipid damage and expansion of cell death

Neurons and cardiac and renal tissues are highly sensitive to membrane lipid peroxidation. Once GPX4 function becomes insufficient, injury can rapidly expand. Therefore, GPX4-protective enhancement strategies have high potential in such diseases.

(2) GPX3 can serve as an auxiliary node for systemic injury assessment and intervention

For organ injuries accompanied by amplified inflammation and increased oxidative burden in body fluids, the peripheral monitoring value and protective potential of GPX3 are more readily translatable into clinical evaluation indices.

5.3 Network-Reconstruction Strategies in Inflammatory and Metabolic Diseases

(1) GPX2 and epithelial barrier protection are suitable for inflammation-related injury

In the context of intestinal inflammation, mucosal injury, and barrier dysfunction, maintaining GPX2-related defense capacity helps reduce local oxidative damage and persistence of inflammation.

(2) GPX7/8 are suitable for incorporation into ER stress-related strategies

In obesity, metabolic syndrome, and chronic inflammation, ER stress and oxidative stress often coexist. In such settings, the proteostasis network connected by GPX7/8 may become a more effective point of intervention than traditional free radical scavenging.

VI. Key Pathways, Targets, and Evaluation Indicators in Research and Translation

6.1 Major Research Pathways

(1) The GPX4-GSH-lipid peroxidation-ferroptosis pathway

This pathway is currently the most important mechanistic axis in GPX research and is applicable to tumors, neural injury, ischemia-reperfusion, and acute organ injury.

(2) The GPX1/2-ROS buffering-stress tolerance pathway

This pathway is more suitable for explaining basal antioxidant defense, epithelial barrier stability, and tumor stress adaptation.

(3) The GPX3-body fluid antioxidation-organ protection pathway

This pathway emphasizes control of oxidative burden in the circulation and the value of peripheral injury stratification.

(4) The GPX7/8-ER stress-proteostasis pathway

This pathway helps explain, at a higher level, the coupling between oxidative stress and defects in protein processing.

6.2 Key Targets

(1) Direct targets

GPX1, GPX2, GPX3, GPX4, GPX7, GPX8.

(2) Parallel regulatory targets

GSH synthesis and regeneration systems, lipid remodeling-related enzymes, iron metabolism-related molecules, and ER stress regulatory nodes.

(3) Upstream regulatory targets

Selenium metabolism-related factors, the NRF2 pathway, nutritional state regulators, and oxidative stress-sensing networks.

6.3 Commonly Used Evaluation Indicators

(1) Detection of GPX expression and activity

In research, GPX1, GPX2, GPX3, GPX4, GPX7, and GPX8 mRNA and protein expression are usually measured first. Common methods include qPCR, Western blotting, immunohistochemistry, and immunofluorescence. At the same time, total GPx enzymatic activity and the GSH/GSSG ratio are often assessed to determine whether expression changes truly correspond to functional changes.

(2) Detection of oxidative stress and lipid peroxidation

In GPX family research, total ROS, hydrogen peroxide levels, and the degree of lipid peroxidation are commonly measured. Typical indicators include DCFH-DA for ROS detection and MDA and 4-HNE for terminal products of lipid peroxidation. When the research focus is GPX4, C11-BODIPY is also often used to detect lipid ROS because such indices more directly reflect oxidative damage to membrane lipids.

(3) Ferroptosis-related detection

In GPX4-related studies, Fe2+ levels, ferroptosis-related molecules such as ACSL4 and SLC7A11, and the rescue response of cells to Ferrostatin-1, Liproxstatin-1, or Deferoxamine are also commonly measured. If the induced injury can be reversed by these molecules, it usually indicates relatively clear ferroptotic characteristics.

(4) Detection of cellular injury and survival

Common methods include CCK-8, MTT, LDH release, and colony formation assays, which are used to evaluate changes in cellular tolerance to oxidative stress or drug treatment after GPX modulation. When necessary, methods such as Annexin V/PI staining should also be combined to distinguish among apoptosis, necrosis, ferroptosis, and other cell death modes.

(5) Detection of organ injury and tissue protection

In animal- or tissue-level studies, H&E staining, TUNEL staining, and immunohistochemistry are commonly combined to observe tissue injury, cell death, and changes in key proteins. At the same time, organ-specific functional indicators should be selected according to the organ involved, such as Scr and BUN for the kidney, ALT and AST for the liver, and functional readouts for myocardial and neural tissues.

(6) Detection of ER stress and proteostasis

When GPX7 or GPX8 is the object of study, indicators related to ER stress and protein folding, such as BiP, CHOP, XBP1s, and PDI, are commonly added. This better reflects their functional characteristics in proteostasis and stress regulation.

Table 2. Pathways, Targets, and Detection Indicators in GPX Family Research

Research Direction	Major Pathway	Key Targets	Common Detection Indicators
Ferroptosis regulation	GPX4-GSH-lipid peroxidation axis	GPX4, GSH system, iron metabolism-related factors	Lipid ROS, membrane damage, cell viability, iron levels
Basal antioxidant defense	GPX1/2-ROS buffering axis	GPX1, GPX2, NRF2	ROS, enzymatic activity, inflammatory readouts, epithelial injury phenotype
Peripheral organ protection	GPX3-body fluid antioxidation axis	GPX3, circulating oxidative stress indicators	Plasma GPX3, organ function, inflammation and fibrosis indicators
Proteostasis regulation	GPX7/8-ER stress axis	GPX7, GPX8, ER stress-related factors	CHOP, BiP, protein aggregation, Ca2+ homeostasis
Strategy development	Selenium supplementation, GSH restoration, NRF2 activation, GPX mimetics	Selenium metabolism, GSH system, NRF2, GPX4	Restoration of enzyme activity, alleviation of oxidative injury, tissue-protective phenotypes

VII. Experimental Molecules and Research Tools for GPXs Family Studies

7.1 Common Mechanistic Perturbation Molecules and Experimental Reagents for GPXs Family Research

Name	CAS No.	Experimental Step	Key Use	Notes for Use
Ebselen	60940-34-3	GPX mimetic research	Used as a classical GPX mimetic to establish enzyme-like antioxidant protection models	More suitable for GPX function substitution, peroxide clearance, and protective controls, and should not be directly equated with GPX4-specific enhancement
RSL3	1219810-16-8	GPX4 inhibition and ferroptosis induction	Directly weakens the GPX4-related defense line and is used to establish lipid peroxidation-dependent injury models	Suitable for pairing with Ferrostatin-1 or Liproxstatin-1 to determine whether cell death exhibits ferroptotic characteristics
ML162	1035072-16-2	GPX4 inhibition research	Used as a common GPX4 inhibitor to verify GPX4-dependent survival	Suitable for parallel use with RSL3 to improve the robustness of GPX4-related mechanistic conclusions
ML-210	1360705-96-9	Selective GPX4 inhibition research	Used to establish a clearer GPX4 inhibition model	Suitable for pharmacological stratification studies and for combination with upstream GSH depletion strategies
JKE-1674	2421119-60-8	GPX4 inhibition research	Used as the active metabolite of ML-210 to strengthen validation of GPX4 dependence	More suitable for supplementary ML-210-related mechanistic studies and sensitivity comparisons
FIN56	1083162-61-1	GPX4 functional attenuation research	Induces ferroptosis by lowering GPX4 protein and simultaneously engaging lipid metabolic pathways	More suitable for establishing non-single-site, comprehensive lipid peroxidation injury models
Ferrostatin-1	347174-05-4	Ferroptosis rescue experiments	Used as a classical ferroptosis inhibitor to reverse lipid peroxidation injury induced by RSL3, Erastin, and related agents	Suitable as a mechanistic rescue molecule rather than as a simple broad-spectrum antioxidant control
Liproxstatin-1	950455-15-9	Lipid peroxidation chain termination research	Used to inhibit amplification of lipid peroxidation and protect cells with GPX4 imbalance	More suitable for tissue protection, ischemia-reperfusion, and in vivo rescue settings
Erastin	571203-78-6	system x(c)- inhibition and GSH depletion	Indirectly weakens the GPX4 defense line by inhibiting cystine uptake	Suitable for establishing upstream supply-restricted ferroptosis models and for paired validation with Ferrostatin-1
L-Buthionine-(S,R)-sulfoximine (BSO)	83730-53-4	GSH depletion research	Inhibits gamma-glutamylcysteine synthesis and reduces GSH synthesis capacity	Suitable for combination with GPX4 inhibitors to amplify oxidative pressure and assess GSH dependence
N-Acetyl-L-cysteine (NAC)	616-91-1	Reducing power supplementation research	Used as a cysteine donor and common antioxidant molecule to restore GSH-related defenses	More suitable as a functional rescue or control molecule for distinguishing supply restriction from enzyme dysfunction
Reduced glutathione (GSH)	70-18-8	GSH supplementation and enzymatic activity research	Used as an electron donor for GPXs to supplement reducing conditions or establish in vitro activity systems	Suitable for synchronous detection with GSSG to analyze the GSH/GSSG balance and GPX execution capacity
Oxidized glutathione (GSSG)	27025-41-8	Redox state evaluation	Used as oxidized glutathione to establish or assess oxidative stress conditions	Commonly paired with GSH to reflect the cellular reducing state and pressure on GPX-related defense lines
Sodium selenite	10102-18-8	Selenium supplementation research	Used to increase selenium supply and support the synthesis and functional recovery of selenoprotein-type GPXs	Suitable for selenium deficiency models, low-enzyme-activity settings, and long-term nutritional support designs
L-Selenomethionine	3211-76-5	Selenoprotein enhancement research	Used as a common organic selenium source to evaluate the effects of selenium supplementation on GPX expression and function	More suitable for chronic treatment and nutritional support designs, facilitating observation of selenoprotein recovery trends
Sulforaphane	4478-93-7	NRF2 network enhancement research	Used as a Keap1-NRF2 signaling activator to enhance endogenous antioxidant networks	More suitable for chronic oxidative stress and network-enhancing antioxidant designs
Dimethyl fumarate	624-49-7	NRF2/GSH network research	Used to activate antioxidant- and immune-regulation-related pathways and enhance GSH-related defense	Suitable for use together with GPX expression, GSH status, and inflammatory readouts
tert-Butylhydroquinone (tBHQ)	1948-33-0	Antioxidant network activation research	Commonly used as a classical chemical inducer to activate endogenous antioxidant responses	More suitable as an NRF2-related positive control rather than a GPX-specific tool molecule
MitoTEMPO	1569257-94-8	Mitochondrial oxidative stress control	Used to distinguish the relationship between mitochondrial ROS and GPX imbalance	Suitable for mitochondrial injury models related to GPX1 or GPX4
Deferoxamine mesylate	138-14-7	Iron-dependent injury control	Used as an iron chelator to reduce iron-dependent lipid peroxidation pressure	Suitable for use with ferroptosis inducers to confirm iron dependence
Trolox	53188-07-1	Positive antioxidant control	Used as a water-soluble vitamin E derivative to establish oxidative injury inhibition control systems	Suitable as a broad-spectrum antioxidant control in GPX-related research
alpha-Tocopherol	10191-41-0	Lipid peroxidation inhibition research	Used as a lipid-soluble antioxidant to inhibit membrane lipid oxidative injury	More suitable as a membrane-protective control molecule in GPX4/lipid peroxidation studies
Coenzyme Q10	303-98-0	Membrane and mitochondrial antioxidation research	Used to support the antioxidant capacity of membrane systems and mitochondria	More suitable as an auxiliary molecule related to membrane lipid protection and energy metabolism
Idebenone	58186-27-9	Neuroprotection and mitochondrial oxidative stress research	Used as a CoQ10 analogue to evaluate protection against membrane and mitochondrial oxidative injury	More suitable for neural systems and organ injury models with high oxidative burden

7.2 Representative Experimental Product Portfolio for GPXs Family Research

(1) Molecules related to GPX4 regulation and ferroptosis research

Catalog No.	Name	Grade and Purity	Applicable Research Direction/Use	Notes for Use
R302648	RSL3	Moligand™, ≥98%	Classical GPX4 inhibitor; used to establish lipid peroxidation amplification and ferroptosis induction models	Suitable as the first-choice positive tool molecule for GPX4-dependence research and can be used together with rescue experiments
G1424411	GPX4 activator 1	—	Used to observe the protective effects of GPX4 enhancement on lipid peroxidation and organ injury models	More suitable for reverse validation with RSL3 or oxidative injury models
G1424743	GPX4 activator 2	—	Used for GPX4 functional enhancement, lipid peroxidation inhibition, and protective intervention studies	Suitable for protective evaluation in non-tumor injury settings
G1425057	GPX4-IN-2	≥98%	Small-molecule GPX4 inhibition research; used to supplement validation of GPX4 inhibition with different chemical scaffolds	Suitable for parallel use with RSL3 to reduce bias from a single molecule
G646321	GPX4-IN-3	≥99%	GPX4 inhibition and ferroptosis mechanism research	Suitable for establishing high-purity pharmacological validation systems
G1425056	GPX4-IN-4	≥98%	GPX4 inhibition research; used to evaluate lipid peroxidation and cell death sensitivity	More suitable for dose-gradient and pharmacodynamic comparison studies
G1424748	GPX4-IN-5	≥99%	GPX4 inhibition and tumor oxidative vulnerability research	Suitable for combined design with GSH depletion strategies
G1424671	GPX4-IN-6	≥99%	GPX4 inhibition and ferroptosis induction research	Can be used for cross-validation with other GPX4 inhibitors
P1424746	PROTAC GPX4 degrader-1	≥99%	Used to validate GPX4 dependence at the protein degradation level	Suitable for distinguishing between “enzymatic activity inhibition” and “protein-level depletion” effects

(2) Gene intervention tools for the GPX family

Catalog No.	Name	Applicable Research Direction/Use	Notes for Use
G1473358	GPX1 Human Pre-designed siRNA Set A	GPX1 knockdown; used for basal antioxidant defense and stress tolerance research	Suitable for analyzing the effects of GPX1 on total ROS, hydrogen peroxide, and cell survival
G1486347	GPX2 Human Pre-designed siRNA Set A	GPX2 knockdown; used for epithelial barrier, inflammation, and mucosal oxidative injury research	More suitable for intestinal inflammation and epithelial repair models
G1473914	GPX3 Human Pre-designed siRNA Set A	GPX3 knockdown; used for extracellular antioxidation and organ protection mechanism research	Suitable for designs combined with body-fluid samples or secreted protein detection
G1491190	GPX4 Human Pre-designed siRNA Set A	GPX4 knockdown; used to verify the direct regulation of lipid peroxidation and ferroptosis by GPX4	Suitable for use together with indices such as C11-BODIPY, MDA, and 4-HNE
G1471777	GPX7 Human Pre-designed siRNA Set A	GPX7 knockdown; used for ER stress and proteostasis research	Suitable for use together with BiP, CHOP, XBP1s, and related indicators
G1487098	GPX8 Human Pre-designed siRNA Set A	GPX8 knockdown; used for ER stress, protein processing, and chronic inflammation models	More suitable for combined analysis with ER stress readouts

(3) Activity and quantitative detection kits

Catalog No.	Name	Grade and Purity	Applicable Research Direction/Use	Notes for Use
G1505763	Glutathione Peroxidase (GSH-Px) Activity Assay Kit (DTNB, Micro Method)	BioReagent	Total GSH-Px activity detection; suitable for cells and small-volume tissue samples	More suitable for mechanism studies with limited sample amounts
G1505754	Glutathione Peroxidase (GSH-Px) Activity Assay Kit (DTNB, Colorimetric Method)	BioReagent	Total GSH-Px activity detection; suitable for routine tissue and serum samples	Suitable for batch detection in animal experiments
EJ1514953	Human Glutathione Peroxidase 1 (GPX1) ELISA Kit	BioReagent	Human GPX1 quantification; used for evaluation of basal antioxidant status and clinical samples	Suitable for combined analysis with total ROS and GSH/GSSG
EJ1514955	Human Glutathione Peroxidase 4(GPX4) ELISA Kit	BioReagent	Human GPX4 quantification; used for lipid peroxidation and ferroptosis-related research	Suitable for quantification in serum, tissue homogenates, or cell lysates
EJ1512347	Rat Glutathione Peroxidase 3 (GPX3) ELISA Kit	BioReagent	Rat GPX3 quantification; used for organ injury and circulating antioxidant evaluation	Suitable for renal injury, inflammation, and metabolic abnormality models
EJ1512349	Rat Glutathione Peroxidase 4 (GPX4) ELISA Kit	BioReagent	Rat GPX4 quantification; used for tissue protection and ferroptosis evaluation	Suitable for combined use with pathological injury and lipid ROS indicators
EJ1513263	Mouse Glutathione Peroxidase 1 (GPX1) ELISA Kit	BioReagent	Mouse GPX1 quantification; used for basal antioxidation and oxidative injury models	More suitable for screening transgenic or disease models
EJ1515180	Mouse Glutathione Peroxidase 3 (GPX3) ELISA Kit	BioReagent	Mouse GPX3 quantification; used for body-fluid antioxidation and organ protection research	Suitable for plasma/serum and interstitial fluid sample detection
EJ1513264	Mouse Glutathione Peroxidase 4 (GPX4) ELISA Kit	BioReagent	Mouse GPX4 quantification; used for ferroptosis, neural injury, and ischemia-reperfusion models	Suitable for combined use with RSL3 induction or protective intervention experiments

(4) Antibody validation and recombinant proteins

Catalog No.	Name	Grade and Purity	Applicable Research Direction/Use	Notes for Use
Ab105709	Recombinant Glutathione Peroxidase 1 Antibody	Recombinant, ExactAb™, Validated, High Performance, See COA	GPX1 protein detection; for Western blot, IHC, IF, etc.	Suitable for basal antioxidant defense studies and post-knockdown validation
Ab105715	Recombinant Glutathione Peroxidase 2/GPX2 Antibody	Recombinant, ExactAb™, Validated, See COA	GPX2 protein detection; for epithelial barrier and inflammation-related research	Suitable for gastrointestinal and mucosal injury models
Ab105733	Recombinant Glutathione Peroxidase 4 Antibody	ExactAb™, Validated, Recombinant, 0.5 mg/mL	GPX4 protein detection; for the main ferroptosis research axis	Suitable for WB, IHC, IF, and tissue injury evaluation
Ab327014	Recombinant Glutathione Peroxidase 4 Antibody	KD Validation	Validation after GPX4 knockdown/inhibition	Suitable for use together with siRNA or GPX4 inhibitor studies
rp188401	Recombinant Human GPx-7 Protein	Carrier Free, His Tag, ≥90%(SDS-PAGE), See COA	GPX7 functional research; used for ER stress and proteostasis validation	Suitable for in vitro functional supplementation, binding assays, or antibody standard applications
rp220388	Recombinant Human Glutathione Peroxidase 4 Protein	Carrier Free, His Tag, ≥90%(SDS-PAGE), See COA	GPX4 functional research; used for enzymatic evaluation, binding studies, and standard establishment	Suitable for use in inhibitor screening and activity system construction

The GPX family is not a single antioxidant target, but rather a functional system composed of multiple redox regulatory nodes with compartment-specific and disease-scenario-specific characteristics. GPX4 is the core regulator of ferroptosis and membrane lipid injury, GPX1/2 more often undertake basal antioxidation and stress adaptation, GPX3 carries dual significance as a body-fluid protective factor and stratification biomarker, and GPX7/8 extend the research boundary to ER stress and proteostasis. Future development paths with greater translational value should center on clearly defined isoform specialization, disease-scenario stratification, and bidirectional design for both protection and inhibition, so that antioxidant strategies can progress from broad-spectrum reactive oxygen species scavenging toward precise regulation of lipid peroxidation, ferroptosis, and redox homeostasis networks.