Alantolactone inhibits T-cell lymphoma progression by suppressing CD47 expression via the PI3K/AKT and ERK signaling pathways.

T-cell lymphoma (TCL) is a malignant tumor caused by abnormal proliferation of T cells, and its specific pathogenesis remains unclear. Currently, there is still a lack of highly effective therapeutic agents in clinic. As a semi-terpene lactone compound, Alantolactone (ATL) is mainly used to treat diseases such as asthma, and its role in TCL has not been revealed. Here we systematically demonstrated that ATL not only significantly inhibits proliferation, migration, and induces apoptosis in TCL cells in vitro, but also exhibits significant anti-tumor effects in TCL cell line xenograft models with no obvious drug toxicity. Notably, ATL markedly enhance the sensitivity of TCL cells to first-line chemotherapeutic agents such as decitabine. Mechanistically, multi-omics analysis confirmed that ATL restricts TCL progression by negatively regulating the PI3K/AKT and ERK signaling pathway. Additionally, our study also found that ATL-mediated suppression of these pathways leads to significant downregulation of CD47 expression through reducing transcriptional factor c-Myc levels, which in turn enhance the phagocytosis of TCL cells by macrophages. It underscores the potential application of ATL in the immunotherapy of TCL. In summary, our study elucidates that ATL exhibits significant anti-TCL effects both in vitro and in vivo, suggesting its potential as a novel clinical strategy for the treatment of TCL.