CN-120837469-B - Beta-hydroxy-beta-methylbutyric acid as GSDMD inhibitor and application thereof in resisting cell scorch

Abstract

The invention relates to an application of beta-hydroxy-beta-methylbutyric acid (HMB) or a pharmaceutically acceptable salt thereof as an inhibitor of GASDERMIN D (GSDMD) in preparing medicines for resisting cell apoptosis. HMB modulates macrophage apoptosis by blocking GSDMD palmitoylation, and has potential as a novel therapeutic agent for treating inflammatory diseases driven by deregulated apoptosis.

Inventors

• Liang chaoyang
• YANG YUN
• ZHANG JIN
• ZHANG WEIXUN

Assignees

• 中日友好医院(中日友好临床医学研究所)

Dates

Publication Date

20260508

Application Date

20250806

Claims (5)

1. 1. Use of β -hydroxy- β -methylbutyric acid or a pharmaceutically acceptable salt thereof as an inhibitor of GASDERMIN D (GSDMD) in the manufacture of a medicament for use in the treatment or prevention of ischemia reperfusion injury.
2. 2. The use according to claim 1, wherein the pharmaceutically acceptable salt is selected from alkali metal salts and alkaline earth metal salts.
3. 3. The use according to claim 1, wherein the pharmaceutically acceptable salt is a calcium salt or a sodium salt.
4. 4. The use according to claim 1, wherein the β -hydroxy- β -methylbutyric acid or a pharmaceutically acceptable salt thereof inhibits GSDMD-induced apoptosis by blocking palmitoylation of the GSDMD cysteine residue.
5. 5. The use according to any one of claims 1 to 4, wherein the medicament further comprises a pharmaceutically acceptable adjuvant.

Description

Beta-hydroxy-beta-methylbutyric acid as GSDMD inhibitor and application thereof in resisting cell scorch Technical Field The present invention relates to the field of chemical biology. More particularly, the invention relates to the use of beta-hydroxy-beta-methylbutyric acid as an inhibitor of GASDERMIN D (GSDMD) and its anti-apoptotic use. Background Apoptosis is an inflammatory type of programmed cell death characterized by swelling of cells, perforation of membranes, and release of inflammatory cytokines [1] ([ 1] refers to reference 1, hereinafter referred to as "1"), such as interleukin-1 beta (IL-1 beta) and interleukin-18 (IL-18). In response to pathogen challenge, apoptosis can be triggered by classical or non-classical inflammatory small body pathways [2-4]. GASDERMIN (GSDM) D plays a key role in the performance of apoptosis, and the activated GSDMD N Terminal (NT) fragment forms transmembrane pores, mediates cytokine release, and interferes with ion and water homeostasis [5-8]. In the GSDM protein family, GSDMD is widely distributed in most organs and immune cells and is intimately involved in the innate immune response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMP) [9,10]. Excessive apoptosis has been reported to lead to the development of a variety of inflammatory diseases, and significant up-regulation of GSDMD was observed in these diseases, including Inflammatory Bowel Disease (IBD) [11], ischemia reperfusion injury [12], sepsis [13], cancer [14,15], and the like, making GSDMD an attractive target for the treatment of a variety of inflammatory diseases. Inhibition GSDMD-mediated apoptosis is becoming a promising strategy for the treatment of inflammatory diseases, and efforts have recently been made to develop chemical inhibitors targeting GSDMD. Researchers have identified several GSDMD inhibitors such as Necrosulfonamide (NSA) [16], disulfiram (disulfiram, DSF) [17] and dimethyl fumarate (dimethyl fumarate, DMF) [18] and the like. Most of these GSDMD inhibitors show a significant pathological relief in preclinical disease models of sepsis. CN119745860a discloses that small molecule compound SFII as GSDMD inhibitor is capable of resisting cell apoptosis and exerting anti-inflammatory effect to prevent or treat atherosclerosis. However, recent studies have found GDSMD that have a cell-coke-death independent protective function in epithelial cells [19,20], which complicates the selection of GSDMD inhibitors as clinical drugs, particularly for inflammatory diseases with epithelial lesions. Therefore, the development and study of novel GSDMD inhibitors as therapeutic agents for a range of diseases is of great importance. Beta-hydroxy-Beta-methylbutyric acid (HMB) is a biologically active metabolite derived from the essential amino acid leucine, which has been used as a supplement to improve exercise capacity to promote muscle hypertrophy and to enhance muscle strength [21]. Several clinical studies have shown that HMB supplementation is beneficial to both healthy individuals and clinical populations, and that its biosafety has been demonstrated in various populations including athletes, elderly, and clinical patients, such as Chronic Obstructive Pulmonary Disease (COPD) patients or cancer patients [22-25]. Disclosure of Invention As mentioned above, apoptosis is a form of lytic, inflammatory programmed cell death mediated by GASDERMIN proteins, and is associated with the pathogenesis of a variety of inflammatory diseases such as inflammatory bowel disease and ischemia reperfusion injury. GASDERMIN D (GSDMD) is a core executor of cell apoptosis and is a promising therapeutic target, but strategies for safely regulating the activity of the cell apoptosis are yet to be explored. Here we have found that β -hydroxy- β -methylbutyric acid (HMB), a leucine derived metabolite that has proven to be clinically biosafety, is a potent inhibitor of GSDMD-dependent cell apoptosis. Metabonomic analysis of GSDMD -/- and wild-type macrophages showed significant accumulation of HMB during apoptosis of the cell coke. Mechanistically, HMB reduces Akt signaling, inhibits palmitoyl transferase zdhc 7, and thus blocks palmitoylation of GSDMD cysteine residues. This modification is critical for the membrane localization of GSDMD, whose inhibition by HMB would disrupt pore formation, cytokine release and cell apoptosis. In the mouse model, administration of HMB significantly reduced sodium dextran sulfate (DSS) -induced colitis and pulmonary ischemia reperfusion injury, similar to the protective effect of inhibition GSDMD. Our findings not only delineate a metabolite-GSDMD regulatory axis by palmitoylation, but also highlight the potential of HMB (a clinically safe nutritional supplement) as a novel therapeutic agent for the treatment of inflammatory diseases driven by deregulated cell apoptosis. Thus, according to one aspect of the present invention there is provided t