Erianin facilitates pyroptosis in endometrial cancer via targeting m6A reader YTHDF1

Background Endometrial cancer (EC) is a gynecological malignancy that originates from the endometrial epithelium and has a poor prognosis when advanced, recurrent, or metastatic. The limited therapeutic efficacy and severe adverse effects of conventional chemotherapy in advanced EC highlight the urgent need to develop more effective therapeutic drugs. Accumulating clinical evidence has revealed that natural compounds possess pharmacological advantages, including low toxicity and multi-target mechanisms. Erianin is a natural small-molecule compound isolated from Dendrobium chrysotoxum Lindl that has multiple pharmacological effects. However, the effects of erianin on EC have not been confirmed and its anticancer mechanisms remain unclear. Methods Erianin was identified as a potent natural compound against EC through compound library screening. The CCK-8 assays, colony formation assays, Edu experiments, and Live/Dead cell staining assays were utilized to analyze the anti-proliferative activity of erianin. Morphological characteristics, transmission electron microscopy, LDH release assays, and Western blot assays were used to evaluate the activation of pyroptosis. A transcriptome sequencing analysis was performed to identify potential mechanism of erianin. We also synthesized biotin-erianin and used a 20k human proteome microarray to identify its direct targets. Molecular docking and CETSA were used to investigate whether erianin binds to YTHDF1. To evaluate the in vivo therapeutic potential of erianin, we established an EC xenograft model and performed mechanistic investigations incorporating H&E staining, IHC staining, and Western blot assays. Results Our results demonstrated that erianin inhibited the cell proliferation of EC cells and promoted pyroptosis through the caspase-3/GSDME pathway. Mechanistically, we established a crucial role for FOXM1/ RRM2-mediated DNA damage in erianin-induced pyroptosis. Protein microarray revealed that erianin-biotin directly targeted m6A reader YTHDF1. We further confirmed that erianin bound to YTHDF1 by molecular docking and CETSA. Molecular studies indicated erianin inhibited YTHDF1 recognized m6A-modified FOXM1 and promoted FOXM1 mRNA degradation, which leads to DNA damage and caspase-3-mediated GSDME cleavage. Erianin also significantly inhibited EC tumor growth in EC models. Conclusion Erianin directly targets YTHDF1 to suppress the FOXM1/RRM2 axis and consequently promotes caspase-3/GSDME-dependent pyroptosis in EC cells. Our findings provide a new strategy for further clinical exploration of EC. Graphical abstract