CN-121971621-A - High-oxygen lung injury treatment drug based on iron death inhibition, screening method and application

Abstract

The invention relates to a high-oxygen lung injury treatment drug based on iron death inhibition, a screening method and application thereof, and relates to the technical field of biological medicines. The invention makes sure that iron death is one of the key mechanisms of high oxygen lung injury, provides a new target for clinical prevention and treatment, and proves that high oxygen can induce mouse lung microvascular endothelial cells to generate iron death, high oxygen can induce mice to generate acute lung injury, iron death participates in the process, an iron death related signal channel is activated in the high oxygen lung injury, and an iron death inhibitor (such as dexmedetomidine, liproxstatin-1 and deferoxamine) can obviously relieve the high oxygen induced cell injury and lung tissue pathological changes. The target and the biomarker provided by the invention can be used for developing a diagnostic kit for evaluating HALI severity or prognosis, and the established screening model and method can be used for screening novel anti-HALI compounds in a high throughput manner, so that the development process of new drugs is accelerated.

Inventors

• DU QUAN
• CHEN SHIKUN

Assignees

• 重庆医科大学

Dates

Publication Date

20260505

Application Date

20260212

Claims (10)

1. 1. A pharmaceutical composition for preventing or treating a high oxygen lung injury, characterized in that the pharmaceutical composition comprises an iron death inhibitor as an active ingredient.
2. 2. The pharmaceutical composition of claim 1, wherein the iron death inhibitor acts by inhibiting a key regulatory molecule in the iron death pathway selected from at least one of ATF3, SLC7A11, GPX4, keap1, NRF2, HMOX1, cGAS, STING.
3. 3. The pharmaceutical composition according to claim 1 or 2, wherein the iron death inhibitor is at least one selected from Liproxstatin-1, deferoxamine (DFOM), dexmedetomidine (DEX).
4. 4. The pharmaceutical composition of claim 2, wherein the iron death inhibitor acts therapeutically by inhibiting the ATF3/SLC7a11/GPX4 signaling axis, modulating the Keap1/NRF2/HMOX1 signaling axis, or inhibiting the cGAS/STING signaling axis.
5. 5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is an injection, an inhalant, an oral formulation, or a transdermal formulation.
6. 6. Use of an iron death inhibitor for the manufacture of a medicament for the prevention or treatment of hyperoxidative lung injury.
7. 7. The use according to claim 6, wherein the iron death inhibitor is at least one selected from Liproxstatin-1, deferoxamine (DFOM), dexmedetomidine (DEX).
8. 8. A method for screening candidate drugs for preventing or treating high oxygen lung injury, comprising the steps of ‌ (A) Providing a cell or animal model of a hyperoxic lung injury; (b) Administering a test compound to the model; (c) Detecting in the model the level of a biomarker associated with iron death or the expression or activity of the key regulatory molecule of claim 2; (d) Comparing the test result with a control model without the test compound, wherein the test compound is indicated to be a candidate drug for preventing or treating the hyperoxypulmonary injury if the test compound can reduce the level of an iron death-related biomarker, or can down-regulate the expression/activity of at least one of ATF3, keap1, HMOX1, cGAS, STING, and/or can up-regulate the expression/activity of at least one of SLC7A11, GPX4, NRF 2.
9. 9. The method of claim 8, wherein the iron death-related biomarker comprises at least one of intracellular Reactive Oxygen Species (ROS) levels, lipid peroxide levels, glutathione (GSH) levels, intracellular iron ion levels.
10. 10. A kit for assessing the extent of iron death in a hyperoxidative lung injury, comprising reagents for detecting the level of expression of at least one of the key regulatory molecules of claim 2, and/or reagents for detecting the level of at least one of the iron death-related biomarkers of claim 9.

Description

High-oxygen lung injury treatment drug based on iron death inhibition, screening method and application Technical Field The invention relates to the technical field of biological medicines, in particular to a high-oxygen lung injury treatment medicine based on iron death inhibition, a screening method and application. Background High oxygen lung injury (hyperoxia-induced acute lung injury, HALI) is a type of acute lung injury that occurs frequently in anesthesia and in intensive care units, and is one of the common complications of premature infants and low-weight infants in pediatric care units, and in clinic, in the face of emergency situations such as low blood oxygen partial pressure and emergency rescue such as shock in surgery, high-proportion of inhaled oxygen is often required, high-concentration oxygen is also commonly used in intensive care units for preventing hypoxia after surgery, and high-oxygen-mediated oxidative stress can cause organ toxicity processes such as acute lung injury (acute lung injury, ALI), i.e., high-oxygen lung injury (HALI), and the specific molecular mechanism thereof has not yet been fully elucidated, and a specific targeted therapy method is lacking. Iron death (Ferroptosis) is a novel cell programmed regulated death form newly discovered by cell biologists according to basic research results in recent years, is iron ion-dependent, non-apoptosis type cell death characterized by accumulation of lipid peroxide, and an iron death mechanism determines continuous evolution and continuous development modes of various important clinical related diseases, so that deep research on iron death is helpful for people to further define the pathogenesis of the clinical related diseases. The current research on iron death in lung diseases is mainly based on tumor cancers and neurological diseases, but the research on the role of iron death in high-oxygen lung injury is little. Currently, HALI treatments are mostly supportive therapies, and targeted intervention strategies for their core cell death mechanisms remain to be developed. Disclosure of Invention The invention aims at solving the problems and provides a high-oxygen lung injury treatment drug based on iron death inhibition, a screening method and application thereof, and a preparation method and application thereof. In a first aspect the present invention provides a pharmaceutical composition for preventing or treating hyperoxidative lung injury, the pharmaceutical composition comprising an iron death inhibitor as an active ingredient. Preferably, the iron death inhibitor functions by inhibiting a key regulatory molecule in the iron death pathway selected from at least one of ATF3, SLC7A11, GPX4, keap1, NRF2, HMOX1, cGAS, STING. Preferably, the iron death inhibitor is selected from at least one of Liproxstatin-1, deferoxamine (DFOM), dexmedetomidine (DEX). Preferably, the iron death inhibitor exerts a therapeutic effect by inhibiting the ATF3/SLC7A11/GPX4 signaling axis, modulating the Keap1/NRF2/HMOX1 signaling axis, or inhibiting the cGAS/STING signaling axis. ‌ A Preferably, the pharmaceutical composition is an injection, an inhalant, an oral preparation or a transdermal preparation. The second invention of the present invention provides the use of an iron death inhibitor for the manufacture of a medicament for preventing or treating hyperoxidative lung injury. Preferably, in the application technical scheme, the iron death inhibitor is at least one selected from Liproxstatin-1, deferoxamine (DFOM) and Dexmedetomidine (DEX). A third aspect of the present invention provides a method for screening a candidate drug for preventing or treating a high-oxygen lung injury, comprising the steps of ‌ (A) Providing a cell or animal model of a hyperoxic lung injury; (b) Administering a test compound to the model; (c) Detecting in the model the level of a biomarker associated with iron death or the expression or activity of the key regulatory molecule described above; (d) Comparing the test result with a control model without the test compound, wherein the test compound is indicated to be a candidate drug for preventing or treating the hyperoxypulmonary injury if the test compound can reduce the level of an iron death-related biomarker, or can down-regulate the expression/activity of at least one of ATF3, keap1, HMOX1, cGAS, STING, and/or can up-regulate the expression/activity of at least one of SLC7A11, GPX4, NRF 2. Preferably, in the above method embodiment, the iron death-related biomarker comprises at least one of intracellular Reactive Oxygen Species (ROS) level, lipid peroxide level, glutathione (GSH) level, and intracellular iron ion level. ‌ A In a fourth aspect the invention provides a kit for assessing the extent of iron mortality in a hyperoxidative lung injury, characterized in that the kit comprises reagents for detecting the expression level of at least one of the key regulatory molecules described above and/or reagents for