Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 0 0 2026 10 04 1 9 Saeed Mahdianipur Applied Virology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran. Hadi Esmaeili Gouvarchin Ghaleh Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran. Homa Davoodi Cancer research center, Golestan university of medical sciences, Gorgan, Iran Majid Mirzaei Nodoushan Applied Virology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran. 2026 05 23 2026 07 01 Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, frequently complicated by psychiatric comorbidities such as depression. Both conditions share upregulated inflammatory pathways, with the serotonergic system emerging as a critical mediator linking neuroimmune inflammation to tumor biology. While serotonin modulating drugs like phenelzine demonstrate anticancer potential, their efficacy and mechanistic impact in HCC, particularly when combined with standard chemotherapies, like paclitaxel, remain unexplored. Here, we investigated the cytotoxic effects of phenelzine and paclitaxel co-treatment in Hep-G2 cells. Although viability assays confirmed significant synergistic cytotoxicity, molecular analyses revealed a downregulation of classical apoptosis. Co-treatment decreased the BAX/BCL-2 ratio, primarily driven by BCL-2 upregulation. Concurrently, phenelzine co-treatment induced a marked, dose-dependent elevation of pro-inflammatory markers, including NF-κB, COX-2, and iNOS. Given the established role of NF-κB in activating anti-apoptotic pathways, our findings indicate that phenelzine co-administration shifts the mechanism of paclitaxel-induced cell death from classical apoptosis to inflammation-mediated cytotoxicity. This study highlights the complex neuroimmune-oncological crosstalk in HCC and suggests that administration of neuromodulatory drugs in oncology requires careful consideration of their distinct inflammatory implications. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4851 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4851/2428