Repurposed genipin targeting UCP2 exhibits antitumor activity through inducing ferroptosis in glioblastoma

Abstract

Uncoupling protein-2 (UCP2) controls the antioxidant response and redox homeostasis in cancer and is considered a potent molecular target for cancer treatment. However, the specific mechanism of UCP2 inhibition and its role in glioblastoma (GBM) have not yet been elucidated. Here, we attempt to identify a UCP2 inhibitor and study the underlying molecular mechanism in GBM. Bioinformatics analysis and immunohistochemistry are used to validate the high expression of UCP2 in GBM and its prognostic significance. Drug intervention and tumor xenograft experiments are conducted to determine the inhibitory effect of genipin, a UCP2 inhibitor, on UCP2. The mitochondrial membrane potential and key ferroptosis genes are examined to determine the occurrence of ferroptosis. High expression of UCP2 in GBM is associated with poor prognosis, and inhibiting UCP2 can alleviate the malignant behavior of GBM tumors. Genipin can downregulate the expression of GPX4 and upregulate the expression of ACSL4 by inhibiting UCP2, leading to ferroptosis and alleviating the malignant behavior of tumors. In summary, UCP2 is a potential therapeutic target for GBM. Genipin, which targets UCP2, effectively inhibits GBM development by inducing ferroptosis in vivo and in vitro. These findings indicate that genipin treatment based on UCP2 targeting has potential therapeutic applications with a clinical perspective for the treatment of GBM patients.

1. Introduction

Gliomas are tumors of the central nervous system that originate from glial cells, which are nonneural support cells of the brain. Gliomas account for 81% of intracranial tumors and are among the most common primary tumors in adults [1,2]. Glioblastoma (GBM) is the most aggressive and severe form of primary brain tumor and has a poor prognosis. Current treatment options include surgical resection, radiotherapy, and chemotherapy, but the survival rate for patients is low, with less than 5% of patients surviving beyond five years [3–5]. Therefore, identifying key molecules as therapeutic targets and developing effective targeted therapies to improve patient prognosis are crucial [6].

Uncoupling protein-2 (UCP2) belongs to the family of uncoupling proteins (UCPs) [7–9]. UCP2 acts as an antioxidant and inhibits the generation of reactive oxygen species (ROS) in mitochondria [10–12]. Essentially, tumor cells increase the expression of UCP2 to attenuate the cytotoxic effects of ROS by blocking the mitochondrial respiratory process [13]. The gene expression of UCP2 is regulated by various factors in the body. In general, UCP2 responds to unsaturated fatty acids to regulate energy metabolism [14,15]. Studies on UCP2 in tumors have indicated that it influences tumor metabolism through miRNA regulation [16,17]. Additionally, UCP2 is modulated by factors such as ROS, purine nucleotides, and coenzyme Q [11,18,19]. Undoubtedly, UCP2 is a novel metabolic therapeutic target. Research has shown that UCP2 expression is increased in various tumors [20–22]. Its roles in biochemical and physiological functions have been identified as follows: first, it protects cells from oxidative stress; second, UCP2 can modulate tumor progression through alterations in glycolysis, oxidation, and calcium metabolism; and third, it can enhance antitumor immunity in the tumor microenvironment to restrict cancer development [23]. With these multiple intervention directions toward tumor cells, UCP2 can be considered a potential tumor treatment target.