CN-121668284-B - Application of NPC1 protein or reagent for promoting expression thereof in preparation of medicines for treating MASLD

Abstract

The invention discloses application of NPC1 protein or a reagent for promoting expression of the NPC1 protein in preparation of medicines for treating MASLD, belongs to the technical field of biological medicines, and firstly reveals that NPC1 is a key target point of downstream blocking of autophagy flow in MASLD, and finds out a brand-new functional domain, breaks through the traditional cognition of the NPC1 protein serving as cholesterol transport protein, and provides a cooperative treatment scheme of upstream activation and downstream dredging. In vivo experiments prove that the combination strategy or TFEB agonist single drug treatment can obviously reduce liver steatosis, and the TFEB agonist can also effectively improve MASLD related impaired glucose tolerance.

Inventors

• WANG XIAOJING
• NING QIN
• GAO QIANG
• WU WENHUI
• ZHANG SHUHAN
• Hai Suping
• LI XITANG
• YAN WEIMING
• HU JUNJIAN

Assignees

• 华中科技大学同济医学院附属同济医院

Dates

Publication Date

20260512

Application Date

20260210

Claims (3)

1. Use of 1.TFEB activator1 in the manufacture of a medicament for the treatment of MASLD.
2. Use of thioperamide in combination with rapamycin for the preparation of a medicament for the treatment MASLD.
3. 3. A medicament comprising a) an autophagy upstream activator, and b) an NPC1 function enhancer; the autophagy upstream activator is rapamycin and the NPC1 function enhancer is Thioperamide.

Description

Application of NPC1 protein or reagent for promoting expression thereof in preparation of medicines for treating MASLD Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of NPC1 protein or an agent for promoting expression of the NPC1 protein in preparation of a medicament for treating MASLD. Background Fatty liver disease (MASLD) associated with metabolic dysfunction is the most common chronic liver disease worldwide and is characterized by excessive accumulation of liver fat, which can progress to hepatitis, liver fibrosis, cirrhosis or even liver cancer. At present, the clinical intervention is mainly performed through life style, but the compliance of patients is poor, and the curative effect is limited. 2024 FDA approved the first commercial drug to treat MASH-THR-beta agonist Resmetirom, but MASLD patients clinically exhibited differences that reflected the complexity of the disease, and still further explored specific treatment regimens to enrich the clinically alternative treatment regimens. Autophagy is the central process by which cells maintain homeostasis, and its dysfunction is considered to be a key element in the development of MASLD. However, current therapeutic strategies for autophagy for MASLD remain in the research stage. Based on a large number of studies, MASLD has not only insufficient activation of the upstream but also degradation barriers of the downstream, especially the downstream degradation abnormality mechanism of autophagy. Based on such current state of the art, there is currently a lack of effective therapeutic regimens that address both "upstream activation" and "downstream degradation" dual disorders. Therefore, there is an urgent need in the art to find key targets that lead to downstream arrest of autophagy in MASLD, and in combination with the various types of autophagy agonists currently being developed, it is desirable to develop safe and effective therapeutic strategies to restore improvement in autophagy-promoting MASLD disease. Disclosure of Invention The present invention aims to provide the use of NPC1 protein or an agent promoting its expression in the preparation of a medicament for the treatment MASLD, a pharmaceutical combination and strategy for the treatment of MASLD by targeting NPC1 protein to restore autophagy function and by activating TFEB to co-upregulate autophagy activity with NPC1 expression. In order to achieve the above purpose, the present application adopts the following technical scheme: in a first aspect, the invention provides the use of an NPC1 protein or an agent which facilitates expression thereof in the manufacture of a medicament for the treatment MASLD. In the above technical scheme, the NPC1 protein is a biological agent comprising NPC1 protein or a functional domain thereof. In the above embodiments, the agent is a TFEB agonist, which is an mTOR pathway independent agonist. In the above technical scheme, the reagent is a compound capable of up-regulating NPC1 expression or promoting its function. In the above technical solution, the reagent is one of Thioperamide, DOPG, alexidine, vorinostat, GEX1 and A, niacin. In the above embodiments, the agent is used in combination with an autophagy upstream activator for the preparation of a medicament for the treatment MASLD. In the above technical scheme, the autophagy upstream activator is an mTOR inhibitor or an AMPK agonist. In a second aspect, the present invention provides a polypeptide comprising an amino acid sequence as shown in SEQ ID NO.1 or a functional variant thereof, said functional variant having more than 80% homology with the amino acid sequence shown in SEQ ID NO. 1. In a third aspect, the invention provides the use of a polypeptide as described above, a fusion protein thereof or a nucleic acid molecule encoding the same in the manufacture of a medicament for the treatment MASLD. In a fourth aspect, the invention provides a medicament comprising a) an autophagy upstream activator, and b) an NPC1 function enhancer; the autophagy upstream activator is an mTOR inhibitor or an AMPK agonist; The NPC1 function enhancer is a compound capable of up-regulating NPC1 expression or promoting its function, or a biological agent comprising NPC1 protein or a functional domain thereof. The invention has the beneficial effects that: (1) The target is novel, the NPC1 is a key target for downstream blocking of autophagy flow in MASLD is disclosed for the first time, a brand new functional domain is discovered, and the traditional cognition of using the NPC1 as cholesterol transport protein is broken through. (2) Advanced strategy, and proposes a cooperative treatment scheme of upstream activation and downstream dredging. (3) The effect is remarkable, and in vivo experiments prove that the combination strategy or TFEB agonist single drug treatment can remarkably reduce liver steatosis, and the TFEB agonist can also eff