Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, 605 014, India.
Arch Toxicol. 2023 Aug;97(8):2069-2087. doi: 10.1007/s00204-023-03529-w. Epub 2023 May 29.
Acid sphingomyelinase (ASMase) serves as one of the most remarkable enzymes in sphingolipid biology. ASMase facilitates the hydrolysis of sphingomyelin, yielding ceramide and phosphorylcholine via the phospholipase C signal transduction pathway. Owing to its prominent intervention in apoptosis, ASMase, and its product ceramide is now at the bleeding edge of lipid research due to the coalesced efforts of several research institutions over the past 40 years. ASMase-catalyzed ceramide synthesis profoundly alters the physiological properties of membrane structure in response to a broad range of stimulations, orchestrating signaling cascades for endoplasmic reticulum stress, autophagy, and lysosomal membrane permeabilization, which influences the development of hepatic disorders, such as steatohepatitis, hepatic fibrosis, drug-induced liver injury, and hepatocellular carcinoma. As a result, the potential to modulate the ASMase action with appropriate pharmaceutical antagonists has sparked a lot of curiosity. This article emphasizes the fundamental mechanisms of the systems that govern ASMase aberrations in various hepatic pathologies. Furthermore, we present an insight into the potential therapeutic agents used to mitigate ASMase irregularities and the paramountcy of such inhibitors in drug repurposing.
酸性鞘磷脂酶(ASMase)是鞘脂生物学中最显著的酶之一。ASMase 通过磷脂酶 C 信号转导途径促进鞘磷脂的水解,生成神经酰胺和磷酸胆碱。由于其在细胞凋亡中的突出干预作用,ASMase 和其产物神经酰胺由于过去 40 年来几个研究机构的共同努力,成为脂质研究的前沿。ASMase 催化的神经酰胺合成会深刻改变膜结构的生理特性,以响应广泛的刺激,协调内质网应激、自噬和溶酶体膜通透性的信号级联反应,从而影响肝疾病的发展,如脂肪性肝炎、肝纤维化、药物性肝损伤和肝细胞癌。因此,用适当的药物拮抗剂调节 ASMase 活性的潜力引起了极大的兴趣。本文强调了控制各种肝病理中 ASMase 异常的系统的基本机制。此外,我们还深入了解了用于减轻 ASMase 异常的潜在治疗药物,以及此类抑制剂在药物再利用中的重要性。