Cell Metabolism: Team Led by Chaoyun Pan from the Department of Biochemistry, in Collaboration with Junxiu Liu from The First Affiliated Hospital and Qinglei Gao from Tongji Hospital, Discovers Mechanism of Antidepressant in Enhancing Chemosensitivity in
Ovarian cancer is the eighth most common cancer among women worldwide, causing approximately 200,000 deaths annually. Although patients initially respond well to first-line standard treatment (cytoreductive surgery combined with platinum-based chemotherapy), about 70% still experience recurrence within 3 years, and the 5-year survival rate has long remained below 40%. Chemotherapy resistance, particularly due to enhanced DNA homologous recombination (HR) repair capability in tumor cells, is a major reason for treatment failure and patient mortality.
Recent research focusing on the gene regulation, protein modification, and metabolic reprogramming within tumor cells has made significant breakthroughs in understanding the molecular mechanisms of HR repair. However, cancer is a systemic disease, and patient prognosis is closely related to the overall systemic state. In particular, how the overall body system and its complex interactions with the tumor microenvironment influence tumor cell DNA damage repair capacity and chemotherapy outcomes remains a key scientific question requiring in-depth investigation.
Recently, the research team led by Professor Chaoyun Pan from the Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, in collaboration with the gynecology teams of Professor Junxiu Liuand Associate Researcher Jie Li from The First Affiliated Hospital of Sun Yat-sen University, and Professor Qinglei Gao's team from the Gynecology Department of Tongji Hospital, Huazhong University of Science and Technology, published a study titled "Serotonin-licensed macrophages potentiate chemoresistance via inositol metabolic crosstalk in ovarian cancer"inCell Metabolism . This research reveals for the first time the mechanism by which peripheral serotonin (5-HT) enhances DNA homologous recombination repair in tumor cells via tumor-associated macrophages (TAMs), leading to chemotherapy resistance in ovarian cancer. The study innovatively proposes the potential therapeutic strategy of using the commonly prescribed antidepressant fluoxetine (an SSRI) as a chemosensitizer.
The research team constructed a high-grade serous ovarian cancer mouse model mimicking the clinical evolution of drug resistance. Combining single-cell sequencing and metabolomics analysis, they found that serotonin released by platelets infiltrating the tumor acts on a specific macrophage subpopulation expressing the receptor HTR7. This subsequently activates the HTR7-PLC-Ca²⁺ signaling axis, stimulating these macrophages to secrete a large number of extracellular vesicles. These vesicles deliver key enzymes of inositol metabolism (such as PI4K2A, ITPKC) to tumor cells, leading to a significant increase in the level of inositol-1,3,4,5-tetrakisphosphate (IP4) within the tumor cell nucleus. Nuclear IP4 directly binds to MRE11, enhancing MRE11-DNA affinity, thereby boosting the HR repair capacity of tumor cells and causing resistance to platinum-based drugs and PARP inhibitors.
The team discovered that using the widely prescribed selective serotonin reuptake inhibitor (SSRI) fluoxetine to lower peripheral serotonin levels effectively inhibits the activation and vesicle secretion of HTR7⁺ macrophages, reduces inositol metabolism and HR repair levels in tumor cells, and consequently enhances tumor sensitivity to chemotherapy. In various mouse models and patient-derived tumor xenograft models, the combination of fluoxetine with chemotherapy significantly delayed tumor recurrence, reduced tumor burden, and did not increase obvious toxic side effects.
This study not only reveals for the first time a cross-system regulatory axis involving "neurotransmitter-immune cell-metabolic crosstalk-tumor DNA damage repair," but also proposes a potential application strategy for SSRIs as chemosensitizers. The research team will further actively promote related clinical trials to verify the efficacy and safety of the "chemotherapy + SSRI maintenance" regimen in ovarian cancer patients.
Professor Chaoyun Pan from Zhongshan School of Medicine, Sun Yat-sen University; Professor Junxiu Liu from the Gynecology Department of The First Affiliated Hospital; Associate Researcher Jie Li; and Professor Qinglei Gao from Tongji Hospital, Huazhong University of Science and Technology are the co-corresponding authors of this paper. Co-first authors include Associate Researcher Jie Li, postdoctoral fellow Jingyi Lu, doctoral students Cuimiao Zheng and Xi Huang from Zhongshan School of Medicine, and master's student Haoyuan Li from The First Affiliated Hospital. This research was supported by the National Natural Science Foundation of China Youth Program, the Ministry of Science and Technology's Key Special Project on "Reproductive Health and Women & Children's Health Security," and was completed utilizing platforms such as the Advanced Technology Research Institute of Zhongshan School of Medicine - The First Affiliated Hospital, the Metabolomics Research Center and the Laboratory Animal Center of Sun Yat-sen University, and the National Clinical Research Center for Gynecological and Obstetric Diseases at Tongji Hospital, Huazhong University of Science and Technology.
