Key Takeaways & Executive Findings
- •• Ivermectin suppresses ESCC growth by activating the ATF4-mediated ER stress-autophagy pathway. • Transcriptome analysis identifies ATF4 and DDIT3 as key mediators of ivermectin-induced ER stress. • Ivermectin treatment inhibits ESCC xenograft tumor growth in nude mice, demonstrating in vivo efficacy. • Ivermectin represents a promising repurposed drug candidate for ESCC therapy.
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common forms of malignancy worldwide. However, there is currently a lack of effective chemotherapeutic drugs for ESCC. Ivermectin is a broad-spectrum antiparasitic drug with notable antitumor activity. However, the cellular and molecular mechanisms by which ivermectin inhibits cancer growth remain unclear. In this study, we elucidate the role of ivermectin in ESCC suppression by activating the endoplasmic reticulum (ER) stress and autophagy pathways. In transcriptome analyses, we find that activating transcription factor 4 (ATF4) and DNA damage inducible transcript 3 (DDIT3) are involved in the activation of ER stress by ivermectin. Moreover, ivermectin treatment suppresses the growth of ESCC xenograft tumors in nude mice. Taken together, our results establish the antitumor molecular role of ivermectin in targeting the ER stress-autophagy pathway and suggest that ivermectin is a potential drug candidate for the treatment of ESCC.
1. Introduction
Esophageal cancer is a serious malignant gastrointestinal disease [1], with a global incidence of approximately 500,000 new cases per year, and more than half of these cases occur in China [2]. Esophageal squamous cell carcinoma (ESCC) is the main pathological type and accounts for approximately 90% of all esophageal cancer cases in China [3]. The primary treatment for esophageal cancer is surgery. However, due to a lack of early diagnosis, chemotherapy is an important option for the treatment of many inoperable patients [4]. Chemotherapy is associated with many side effects because of the side effects of the many currently used drugs, highlighting the need for new therapeutic agents.
Ivermectin is a safe and efficacious drug approved by the Food and Drug Administration (FDA) for clinical application. Ivermectin has the highest antiparasitic activity, is safe among avermectins, and has been studied as an antiviral or antineoplastic alternative [5,6]. As an antiparasitic drug, ivermectin primarily antagonizes the closure of glutamate-gated chloride channels, causing hyperpolarization of nerve and muscle cells in invertebrates, which in turn paralyzes the pharynx and leads to death [7]. As an alternative antiviral agent, ivermectin inhibits the importin α/β1-mediated nuclear import of viral proteins [8,9]. Many studies have shown that ivermectin exerts antitumor effects on cancers [10,11]. However, the antitumor molecular mechanisms of ivermectin are complex and poorly understood. In addition, studies on the mechanism of action of ivermectin in ESCC are scarce, and the potential benefits of ivermectin in ESCC therapy are underexplored.
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Huiyang Liu, Zhirong Chai, Ya Gao, Yanming Wang, Mengmeng Lu (2026). Ivermectin inhibits the growth of ESCC by activating the ATF4-mediated endoplasmic reticulum stress-autophagy pathway. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024210
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that ivermectin inhibits the growth of esophageal squamous cell carcinoma (ESCC) by activating the ATF4-mediated endoplasmic reticulum (ER) stress-autophagy pathway, both in vitro and in vivo.
How does ivermectin exert its antitumor effects in ESCC?
Ivermectin activates ER stress, leading to increased expression of ATF4 and DDIT3, which in turn triggers autophagy and suppresses tumor growth.
What is the significance of this research?
This research provides evidence that ivermectin, an FDA-approved antiparasitic drug, could be repurposed as a potential therapeutic agent for ESCC, addressing the need for effective chemotherapeutic options.
What experimental models were used?
The study used transcriptome analyses and xenograft tumor models in nude mice to evaluate the effects of ivermectin on ESCC.
What are the key molecular targets of ivermectin in ESCC?
The key molecular targets include ATF4 and DDIT3, which are involved in the ER stress response and autophagy pathway.
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