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The tumor microenvironment (TME) is related to chronic inflammation and is currently identified as a risk factor for the occurrence and development of endometrial cancer (EC). Pyroptosis is a new proinflammatory form of programmed cell death that plays a critical role in the progression of multiple diseases. However, the important role of pyroptosis in high‐glucose (HG)‐related EC and the underlying molecular mechanisms remain elusive. In the present study, transcriptome high‐throughput sequencing revealed significantly higher hexokinase domain‐containing 1 (HKDC1) expression in EC patients with diabetes than in EC patients with normal glucose. Mechanistically, HKDC1 regulates HG‐induced cell pyroptosis by modulating the production of reactive oxygen species and pyroptosis‐induced cytokine release in EC. In addition, HKDC1 regulates TME formation by enhancing glycolysis, promoting a metabolic advantage in lactate‐rich environments to further accelerate EC progression. Subsequently, miR‐876‐5p was predicted to target the HKDC1 mRNA, and HOXC‐AS2 was identified to potentially inhibit the miR‐876‐5p/HKDC1 axis in regulating cell pyroptosis in HG‐related EC. Collectively, we elucidated the regulatory role of the HOXC‐AS2/miR‐876‐5p/HKDC1 signal transduction axis in EC cell pyroptosis at the molecular level, which may provide an effective therapeutic target for patients with diabetes who are diagnosed with EC.

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Highlights Icariin protects against rotenone-induced neuronal cell injury in vitro and in vivo. Icariin improves mitochondrial respiration in neuronal cells damaged by rotenone Icariin modulates phosphorylation of mTOR. Icariin attenuates accumulation of p62 caused by rotenone. Upregulation of autophagic flux is involved in the protective action of icariin.

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