The study, led by Xiaoge Zhang, Xiaoyun Wang, Na Li, Qunying Han and Zhengwen Liu, analyzed the records of 1,141 patients with advanced hepatocellular carcinoma who had received best supportive care, meaning treatment aimed at relieving symptoms rather than attacking the tumor directly. Among these patients, 102 had been given 5-HT3 receptor antagonists, drugs that are routinely prescribed to control nausea and vomiting, particularly during chemotherapy or in the course of supportive management of advanced cancer.

Serotonin, chemically known as 5-hydroxytryptamine or 5-HT, is best known as a neurotransmitter that regulates mood, appetite and gut motility. But its influence extends well beyond the brain and digestive tract. Serotonin signaling has been implicated in hepatocarcinogenesis, the process by which normal liver cells transform into cancerous ones. Serotonin receptors on cells can promote proliferation, angiogenesis and tumor progression, which is why drugs that block specific serotonin receptors have long been suspected of having potential anticancer properties.

When the researchers compared overall survival between patients who received 5-HT3 receptor antagonists and those who did not, the difference was striking. Users of the drugs had a significantly reduced risk of death, with a hazard ratio of 0.690, meaning their mortality risk was roughly 31 percent lower than that of nonusers. The 95 percent confidence interval ranged from 0.546 to 0.871, and the result was statistically significant with a p value of 0.002.

Because patients who receive anti-nausea medications may differ systematically from those who do not, in terms of disease severity, performance status or other treatments received, the team employed propensity score matching, a statistical technique designed to mimic the conditions of a randomized controlled trial using observational data. After matching 89 patients who used the drugs with 161 comparable nonusers, the survival advantage persisted. In this matched cohort, the hazard ratio fell to 0.615, with a confidence interval of 0.457 to 0.829 and a p value of 0.001, indicating that the association was unlikely to be explained by imbalances in baseline characteristics alone.

The findings held up in subgroup analyses as well. Among patients whose liver cancer was associated with hepatitis B virus infection, the dominant cause of hepatocellular carcinoma in China where the study population was drawn, the survival benefit of 5-HT3 receptor antagonist use remained evident. This consistency across a clinically important subgroup strengthens the case that the observed effect is not an artifact of the broader patient mix.

Perhaps the most intriguing results emerged when the researchers examined individual drugs within the class. Tropisetron, one of the second-generation setrons, showed a particularly pronounced effect. After propensity score matching, the five-year overall survival rate among tropisetron users was 23.7 percent, compared with just 10.9 percent among nonusers, a difference that was statistically significant with a p value of 0.004. For a disease in which five-year survival in the advanced stage is typically measured in single digits, a more than doubling of long-term survival in the matched cohort is a remarkable signal.

When the team applied Cox regression analysis, a statistical method that identifies factors independently associated with prognosis, both ondansetron and tropisetron emerged as independent predictors of improved survival. Ondansetron use carried a hazard ratio of 0.603, with a confidence interval of 0.365 to 0.995 and a p value of 0.048, while tropisetron performed even better, with a hazard ratio of 0.477, a confidence interval of 0.299 to 0.759 and a p value of 0.002. In practical terms, patients receiving either of these drugs had roughly half the mortality risk of comparable patients who did not receive them.

The biological rationale for these findings is grounded in a growing body of laboratory research. Serotonin can stimulate tumor cell proliferation and promote the formation of new blood vessels that feed growing tumors, processes mediated in part through serotonin receptors expressed on tumor and endothelial cells. Blocking the 5-HT3 receptor subtype may therefore interfere with signaling pathways that support tumor growth and spread. Some setrons, including tropisetron, have also been shown in preclinical studies to possess anti-inflammatory and immune-modulating properties, raising the possibility that their benefit in liver cancer may extend beyond simple receptor blockade.

The authors conclude that the use of 5-HT3 receptor antagonists is associated with improved overall survival, and that ondansetron and tropisetron in particular were independently associated with better prognosis in patients with advanced hepatocellular carcinoma. As with any observational study, the results demonstrate association rather than causation, and randomized controlled trials would be needed to confirm whether these drugs can truly extend survival. Nevertheless, the prospect that cheap, well-tolerated anti-nausea medications already in the clinic could improve outcomes in one of the world’s most lethal cancers makes this a finding that oncologists and researchers will be watching closely.

Subject of Research: Association of 5-HT3 receptor antagonist use with survival outcomes in advanced hepatocellular carcinoma

Article Title: Association of 5-hydroxytryptamine 3 receptor antagonists with prognosis in patients with advanced hepatocellular carcinoma: A propensity score-matched study

Article References: Zhang, X., Wang, X., Li, N., Han, Q., & Liu, Z. (2026). Association of 5-hydroxytryptamine 3 receptor antagonists with prognosis in patients with advanced hepatocellular carcinoma: A propensity score-matched study. PLOS One, 21(10), e0359798. https://doi.org/10.1371/journal.pone.0359798

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0359798

Keywords: hepatocellular carcinoma, 5-HT3 receptor antagonists, serotonin, ondansetron, tropisetron, overall survival, propensity score matching, liver cancer, hepatitis B, supportive care, Cox regression, drug repurposing