Oncogene　E6　plays　a　critical　role　in　the　development　and　progression　of　esophageal　cancer　caused　by　human　papillomavirus　(HPV)　infection.　Alpha-ketoglutarate　(AKG)　is　a　key　metabolite　in　the　tricarboxylic　acid　cycle　and　has　been　widely　used　as　a　dietary　and　anti-ageing　supplement.　In　this　study,　we　found　that　treating　esophageal　squamous　carcinoma　cells　with　a　high　dose　of　AKG　can　induce　cell　pyroptosis.　Furthermore,　our　research　confirms　that　HPV18　E6　inhibits　AKG-induced　pyroptosis　of　esophageal　squamous　carcinoma　cells　by　lowering　P53　expression.　P53　downregulates　malate　dehydrogenase　1　(MDH1)　expression;　however,　MDH1　downregulates　L-2-hydroxyglutarate　(L-2HG)　expression,　which　inhibits　a　rise　in　reactive　oxygen　species　(ROS)　levels-as　L-2HG　is　responsible　for　excessive　ROS.　This　study　reveals　the　actuating　mechanism　behind　cell　pyroptosis　of　esophageal　squamous　carcinoma　cells　induced　by　high　concentrations　of　AKG,　and　we　posit　the　molecular　pathway　via　which　the　HPV　E6　oncoprotein　inhibits　cell　pyroptosis.