Targeting tumor metabolism: The dual attack of emodin on glycolysis and oxidative phosphorylation in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) exhibits elevated death rate and varying resistance to multiple chemotherapeutic agents. Emodin, a key constituent of rhubarb, has demonstrated anticancer activities in colorectal and breast cancers. However, its application and mechanism in ESCC await full clarification. This study investigates emodin's inhibitory impacts on ESCC in vitro and in vivo and explores its underlying molecular mechanisms, with the aim of identifying a potential candidate for ESCC treatment. To explore the mechanisms by which emodin acts in ESCC, network pharmacology, bioinformatics analysis, proteomic profiling, and Seahorse assays were employed to assess alterations in cellular energy metabolism. The expression extent of the end result markers and pathway proteins induced by emodin were assessed using Western blotting. To evaluate the potential toxicity and antitumor efficacy of emodin in ESCC, a xenograft tumor model was utilized in vivo. Emodin inhibited ESCC cell proliferation, facilitated intrinsic apoptosis, and induced G2/M phase arrest. Proteomic analysis results showed that emodin disrupted cellular energy metabolism by inhibiting both mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. Network pharmacology and rescue experiments identified the p53 and FOXO signaling pathways as key mediators of these effects. In vivo xenograft experiments further supported the inhibitory activity of emodin in ESCC. Emodin induces intrinsic apoptosis in ESCC cells by simultaneously inhibiting both glycolysis and OXPHOS. These results support emodin's potential as a candidate therapeutic candidate for ESCC.