Abstract

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. CCK-8 assays, colony formation assays, Edu experiments, and Live/Dead cell staining assays were used to analyze the anti-proliferative activity of erianin. Morphological characteristics, transmission electron microscopy, lactate dehydrogenase release assays, and western blot assays were used to evaluate the activation of pyroptosis. A transcriptome sequencing analysis was conducted to identify the potential mechanism of erianin. Biotin–erianin was synthesized and 20-k human proteome microarray was used to identify its direct targets. Molecular docking and cellular thermal shift assays (CETSA) were used to investigate whether erianin would bind to YTH domain family proteins (YTHDF1). To evaluate the in vivo therapeutic potential of erianin, an EC xenograft model was established and mechanistic investigations incorporating hematoxylin and eosin and immunohistochemical (IHC) staining, and western blot assays were conducted. Results Erianin inhibited the cell proliferation of EC cells and promoted pyroptosis through the caspase-3/gasdermin E (GSDME) pathway. Mechanistically, a crucial role for FOXM1/RRM2-mediated DNA damage in er