Open Access
ARTICLE
Esketamine Enhances the Chemosensitivity of Colorectal Adenocarcinoma Cells to 5-Fluorouracil via AMPK/mTOR/HMMR Signaling Pathway
Yuerou Feng, Panpan Tong, Shuwen Fu, Xiaofan Lu, Liquan Zheng, Jielan Lai*, Renchun Lai*
Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
* Corresponding Author: Jielan Lai. Email: 
; Renchun Lai. Email: 
(This article belongs to the Special Issue: Advances and Innovations in Colorectal Cancer Research and Treatment)
Oncology Research https://doi.org/10.32604/or.2025.072563
Received 29 August 2025; Accepted 28 November 2025; Published online 29 December 2025
Abstract
Background: The efficacy of standard 5-fluorouracil (5-FU) chemotherapy for colorectal cancer is limited by drug resistance and adverse effects, prompting research into esketamine, a potent ketamine variant with analgesic, antidepressant, and recently discovered anti-tumor properties, to determine if it can enhance 5-FU’s chemosensitivity. This study investigates whether esketamine synergizes with 5-FU to enhance therapeutic efficacy in colorectal adenocarcinoma cell models. Methods: We performed functional assays to evaluate proliferation (CCK-8), migration (wound healing), invasion (Transwell), and apoptosis (flow cytometry) in colorectal adenocarcinoma cell lines treated with 5-FU alone or in combination with esketamine. Transcriptomic profiling was conducted using RNA sequencing, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was employed to identify critical molecular targets and signaling networks. Protein-level validation of key pathway components was performed via western blotting. Results: Combination therapy with esketamine and 5-FU synergistically inhibited cellular proliferation, migration, and invasion while significantly inducing apoptosis compared to monotherapy. Mechanistically, esketamine potentiated 5-FU-driven AMP-activated protein kinase (AMPK) phosphorylation, leading to inhibition of both mammalian target of rapamycin (mTOR) and hyaluronan-mediated motility receptor (HMMR). Conclusion: Esketamine enhances 5-FU chemosensitivity in colorectal adenocarcinoma by activating the AMPK/mTOR/HMMR signaling axis, thereby suppressing tumor progression and metastatic potential. These findings position esketamine as a potential adjunctive therapy for 5-FU-based regimens, offering the dual benefit of enhancing chemotherapeutic efficacy while addressing cancer-associated comorbidities including pain and depression.
Keywords
Esketamine; 5-fluorouracil; colorectal adenocarcinoma; chemosensitivity; AMPK/mTOR/HMMR pathway
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