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

SIMPLE SUMMARY: Squalene synthase is a key enzyme that not only participates in the mevalonate pathway, resulting in cholesterol, but also acts as a potential ferroptosis regulator. The synthesis of squalene and its release in the endoplasmic reticulum protects the cell against lipid peroxidation, resulting in cell survival. We aimed to investigate the therapeutic potential of this enzyme based on its biochemical structure, reaction mechanism, significance in diseases, and relation to ferroptosis. In addition, we compiled the known squalene synthase inhibitors, aiming to provide useful information for researchers and to encourage the conduction of more studies on the therapeutics of squalene synthase. 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.