Rong Zhao

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 erianin-induced pyroptosis was established. Protein microarrays indicated that erianin–biotin directly targeted the m6A reader, YTHDF1. Erianin was confirmed to bind to YTHDF1 using molecular docking and CETSA. Molecular studies indicated that erianin inhibited YTHDF1, recognized m6A-modified FOXM1, and promoted FOXM1 mRNA degradation, which led to DNA damage and caspase-3-mediated GSDME cleavage. Erianin also substantially inhibited EC tumor growth in EC models. Conclusion: Erianin directly targeted YTHDF1 to suppress the FOXM1/RRM2 axis and consequently promoted caspase-3/GSDME-dependent pyroptosis in EC cells. Our findings provide a new strategy for further clinical exploration of EC. Graphical

Background: Endometrial cancer (EC) as one of the most common gynecologic malignancies is increasing in incidence during the past 10 years. Genome-Wide Association Studies (GWAS) extended to metabolic and protein phenotypes inspired us to employ multiomics methods to analyze the causal relationships of plasma metabolites and proteins with EC to advance our understanding of EC biology and pave the way for more targeted approaches to its diagnosis and treatment by comparing the molecular profiles of different EC subtypes. Methods: Two-sample mendelian randomization (MR) was performed to investigate the effects of plasma metabolites and proteins on risks of different subtypes of EC (endometrioid and nonendometrioid). Pathway analysis, transcriptomic analysis, and network analysis were further employed to illustrate gene-protein-metabolites interactions underlying the pathogenesis of distinct EC histological types. Results: The authors identified 66 causal relationships between plasma metabolites and endometrioid EC, and 132 causal relationships between plasma proteins and endometrioid EC. Additionally, 40 causal relationships between plasma metabolites and nonendometrioid EC, and 125 causal relationships between plasma proteins and nonendometrioid EC were observed. Substantial differences were observed between endometrioid and nonendometrioid histological types of EC at both the metabolite and protein levels. The authors identified seven overlapping proteins (RGMA, NRXN2, EVA1C, SLC14A1, SLC6A14, SCUBE1, FGF8) in endometrioid subtype and six overlapping proteins (IL32, GRB7, L1CAM, CCL25, GGT2, PSG5) in nonendometrioid subtype and conducted network analysis of above proteins and metabolites to identify coregulated nodes. Conclusions: Our findings observed substantial differences between endometrioid and nonendometrioid EC at the metabolite and protein levels, providing novel insights into gene-protein-metabolites interactions that could influence future EC treatments.