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Increasing evidence demonstrates that glyoxal exacerbates the development and progression of diabetic nephropathy, but the underlying mechanisms of glyoxal toxicity to human embryonic kidney (HEK293) cells remain unclear. In this work, the molecular mechanisms of glyoxal\u2010induced cytotoxicity in HEK293 cells were explored with network toxicology and cell biology experiments. Network toxicology results showed that oxidative stress and advanced glycation end products (AGEs)\/RAGE signaling pathways played a crucial role in glyoxal toxicity. Next, further validation was performed at the cellular level. Glyoxal activated the AGEs\u2010RAGE signaling pathway, caused the increase of cellular ROS, and activated the p38MAPK and JNK signaling pathways, causing cellular oxidative stress. Furthermore, glyoxal caused the activation of the NF\u2010\u03baB signaling pathway and increased the expression of TGF\u2010\u03b21, indicating that glyoxal caused cellular inflammation. Moreover, glyoxal caused cellular DNA damage accompanied by the activation of DNA damage response pathways. Finally, the mitochondrial apoptosis pathway was activated. The results that obtained in cell biology were consistent with network toxicology, which corroborated each other and together indicated that glyoxal induced HEK293 cells damage via the process of oxidative stress, the AGEs\u2010RAGE pathway, and their associated signaling pathways. This study provides the experimental basis for the cytotoxicity of glyoxal on HEK293 cells.<\/jats:p>","DOI":"10.1002\/tox.23593","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T13:21:45Z","timestamp":1653657705000},"page":"2269-2280","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Investigating the molecular mechanisms of glyoxal\u2010induced cytotoxicity in human embryonic kidney cells: Insights from network toxicology and cell biology experiments"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5521-1783","authenticated-orcid":false,"given":"Dan","family":"Liu","sequence":"first","affiliation":[{"name":"School of life Science Liaoning University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junliang","family":"Chen","sequence":"additional","affiliation":[{"name":"School of life Science Liaoning 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