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CN-122005801-A - RYK and application of ligand-receptor signal axis inhibitor in preparation of drugs for treating fatty liver disease and pulmonary fibrosis

CN122005801ACN 122005801 ACN122005801 ACN 122005801ACN-122005801-A

Abstract

The invention discloses application of RYK and ligand-receptor signal axis inhibitors thereof in preparing medicaments for treating fatty liver diseases and pulmonary fibrosis, and in the technical scheme provided by the invention, RYK receptors are discovered and verified for the first time as functional receptors of secretory extracellular domain (G-ECD) of glycoprotein non-metastatic melanoma protein B, and the G-ECD-RYK signal axis is disclosed as a key mechanism for driving occurrence and development of metabolic dysfunction related fatty liver diseases/hepatitis (MASLD/MASH) and pulmonary fibrosis. The invention discovers the ligand G-ECD of RYK, and establishes the ligand-receptor signal axis of RYK as a brand new drug target with high specificity.

Inventors

  • SONG BAOLIANG
  • XI YUE

Assignees

  • 武汉大学

Dates

Publication Date
20260512
Application Date
20260209

Claims (10)

  1. Use of ryk and ligand-receptor signaling axis inhibitors for the manufacture of a medicament for the treatment of fatty liver disease and pulmonary fibrosis.
  2. 2. The use according to claim 1, wherein the fatty liver disease is MASLD or MASH and the pulmonary fibrosis comprises idiopathic pulmonary fibrosis, environmental factor-induced pulmonary fibrosis, pharmaceutical pulmonary fibrosis, post-infection pulmonary fibrosis and other disease-related pulmonary fibrosis.
  3. 3. The use according to claim 1, wherein the ligand is glycoprotein non-metastatic melanoma protein B or a secreted extracellular domain G-ECD thereof.
  4. 4. The use according to claim 1, wherein the inhibitor blocks the interaction between glycoprotein non-metastatic melanoma protein B and its receptor RYK.
  5. 5. The use according to claim 4, wherein the inhibitor specifically blocks the binding between G-ECD and WIF domain of RYK extracellular segment.
  6. 6. The use according to claim 1, wherein the inhibitor reduces the expression level of RYK or glycoprotein non-metastatic melanoma protein B.
  7. 7. The use according to claim 1, wherein the inhibitor comprises one or more of a vaccine, shRNA, neutralizing antibody, N-acetylgalactosamine-siRNA, small molecule inhibitor, protein inhibitor.
  8. 8. A pharmaceutical composition comprising an inhibitor that targets RYK or an inhibitor that targets G-ECD.
  9. 9. The pharmaceutical composition of claim 8, wherein, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  10. 10. A biomarker panel for detecting the severity of a MASLD/MASH and/or pulmonary fibrosis disease progression, said biomarker panel comprising G-ECD and RYK.

Description

RYK and application of ligand-receptor signal axis inhibitor in preparation of drugs for treating fatty liver disease and pulmonary fibrosis Technical Field The invention relates to the technical field of biological medicines, in particular to application of RYK and a ligand-receptor signal axis inhibitor thereof in preparation of a medicine for treating fatty liver disease and pulmonary fibrosis. Background Metabolic dysfunction-related fatty liver disease/hepatitis (Metabolic dysfunction-associated steatotic LIVER DISEASE/steatohepatitis, MASLD/MASH) has become the most common chronic liver disease worldwide, the prevalence of which rises sharply with the prevalence of obesity and metabolic syndrome, and currently there are many adults affected by this disease worldwide. MASLD/MASH disease spectrum progresses from simple steatosis to steatohepatitis and liver fibrosis, and finally cirrhosis and hepatocellular carcinoma can be developed. Although this disease has become a serious public health problem, specific drugs approved clinically by the FDA or other regulatory agencies are far from adequate. The existing treatment means are only revamping (resmetirom), semaglutin (semaglutide) and lifestyle interventions (diet control and exercise), but have limited efficacy and poor patient compliance. Although various medicines (such as obeticholic acid, liraglutide, vitamin E and the like) enter clinical trial stages in recent years, the medicines have the problems of insufficient curative effect, obvious side effect, unidentified long-term safety and the like. More importantly, the existing therapeutic targets (such as FXR, PPAR and the like) are mainly aimed at metabolic regulation and inflammatory response, and have limited reversing effect on hepatic fibrosis, which is a key driving factor for disease progression. Thus, there is a need to discover new molecular targets and pathogenic mechanisms to develop innovative therapies that can improve steatosis, inflammation and fibrosis simultaneously. Pulmonary fibrosis (Pulmonary fibrosis) is an end-stage manifestation of interstitial lung disease characterized by fibroblast proliferation and massive extracellular matrix deposition, resulting in destruction of lung tissue structures. One common pulmonary fibrosis disease is Idiopathic Pulmonary Fibrosis (IPF), which is primarily developed in the middle-aged and elderly population, but its specific etiology is not yet known. Factors that trigger pulmonary fibrosis are diverse, such as occupational or household environmental factors, drugs, radiation therapy, high concentration oxygen therapy, smoking, disease factors, genetic factors, and the like. Currently, only three drugs, nintedanib (Nintedanib), bringen (nerandomilast) and pirfenidone (Pirfenidone), are available clinically for IPF treatment, but there is limited effectiveness in reversing the fibrosis that has formed. In addition, the side effects of these drugs (such as gastrointestinal reactions, liver dysfunction, light sensitivity, etc.) severely affect the quality of life and medication compliance of patients. More importantly, existing drugs target too wide of targets (e.g., TGF- β signaling pathways, tyrosine kinases, etc.), lack of tissue specificity, resulting in a narrow therapeutic window. For pulmonary fibrosis caused by different causes (such as radioactive lung injury, drug-induced pulmonary fibrosis, fibrosis related to sequelae of new coronavirus infection, and the like), an effective treatment means is lacking at present. Therefore, the common molecular mechanism for occurrence and development of pulmonary fibrosis is deeply explored, a new specific therapeutic target is discovered, and a broad-spectrum therapeutic drug applicable to pulmonary fibrosis with various causes is developed, so that the method has great clinical significance and social value. Disclosure of Invention The invention mainly aims to provide application of a tyrosine kinase-like Receptor (RYK) and a ligand-receptor signal axis inhibitor thereof in preparing medicines for treating fatty liver diseases and pulmonary fibrosis, aims to clarify key pathogenic effects of the RYK receptor and a ligand signal axis thereof in occurrence and development of MASH and pulmonary fibrosis, discloses a novel ligand receptor signal path, provides a brand-new molecular target with potential conversion value for targeted prevention and treatment of MASH and pulmonary fibrosis, and develops innovative therapies capable of simultaneously preventing or treating MASH and pulmonary fibrosis. In order to achieve the above purpose, the invention provides application of RYK and a ligand-receptor signal axis inhibitor thereof in preparing medicines for treating fatty liver diseases and pulmonary fibrosis. Preferably, the fatty liver disease is MASLD or MASH, and the pulmonary fibrosis includes idiopathic pulmonary fibrosis, environmental factor-induced pulmonary fibrosis, pharmaceutical pulmonary f