Unveiling the Therapeutic Potential of Squalene Synthase: Deciphering Its Biochemical Mechanism, Disease Implications, and Intriguing Ties to Ferroptosis

Abstract

Squalene synthase (SQS) has emerged as a promising therapeutic target for various diseases, including cancers, owing to its pivotal role in the mevalonate pathway and the antioxidant properties of squalene. Primarily, SQS orchestrates the head-to-head condensation reaction, catalyzing the fusion of two farnesyl pyrophosphate molecules, leading to the formation of squalene, which has been depicted as a highly effective oxygen-scavenging agent in in vitro studies. Recent studies have depicted this isoprenoid as a protective layer against ferroptosis due to its potential regulation of lipid peroxidation, as well as its protection against oxidative damage. Therefore, beyond its fundamental function, recent investigations have unveiled additional roles for SQS as a regulator of lipid peroxidation and programmed cell death pathways, such as ferroptosis—a type of cell death characterized by elevated levels of lipid peroxide, one of the forms of reactive oxygen species (ROS), and intracellular iron concentration. Notably, thorough explorations have shed light on the distinctive features that set SQS apart from other members within the isoprenoid synthase superfamily. Its unique biochemical structure, intricately intertwined with its reaction mechanism, has garnered significant attention. Moreover, considerable evidence substantiates the significance of SQS in various disease contexts, and its intriguing association with ferroptosis and lipid peroxidation. The objective of this report is to analyze the existing literature comprehensively, corroborating these findings, and provide an up-to-date perspective on the current understanding of SQS as a prospective therapeutic target, as well as its intricate relationship with ferroptosis. This review aims to consolidate the knowledge surrounding SQS, thereby contributing to the broader comprehension of its potential implications in disease management and therapeutic interventions.

Cuproptosis: Unraveling the Mechanisms of Copper-Induced Cell Death and Its Implication in Cancer Therapy

“…Cancer (e.g., lung, colorectal, prostate, breast, melanoma, hepatocellular carcinoma, pancreatic, and skin) [18,38,39].…”

Squalene Epoxidase: Its Regulations and Links with Cancers

“…Following that, isopentenyl pyrophosphate (IPP) and its isomer 3,3-dimethylallyl pyrophosphate are formed by 5-phosphomevalonate decarboxylase; IPP is converted to dimethylallyl pyrophosphate (DMAPP) by isopentanoyl pyrophosphate isomerase, and DMAPP is used together with IPP as the materials for condensation into the fifteen-carbon farnesyl pyrophosphate (FPP) [1,3]. FPP serves as the basic product for squalene production and squalene is formed by the fusion of two FPP molecules; the reaction is catalyzed by squalene synthase [28]. Squalene is then converted to 2,3-epoxysqualene by SQLE, which constitutes the first oxygenation step in cholesterol synthesis [15].…”