SIRT3-IDH2 axis is a target of dietary fructose: implication of IDH2 as a key player in dietary carcinogen toxicity in mice colon

Introduction The potential roles of fructose in colon cancer are growing concerns. Fructose consumption has been linked to oxidative stress and mitochondrial dysfunction, yet its specific molecular mechanisms in colon carcinogenesis remain underexplored. Objectives This study aimed to investigate the molecular mechanisms by which dietary fructose contributes to colon carcinogenesis, focusing on the role of mitochondrial NADP⁺-dependent isocitrate dehydrogenase (IDH2). Methods Using an unbiased multi-omics approach (transcriptomics and proteomics), liver and colon tissues from fructose-fed wild-type (WT) mice were analyzed to identify key genes involved in cancer-related pathways. Human liver transcriptomic data (GSE256398) was analyzed to confirm alterations in aryl hydrocarbon receptor (AhR) signaling and the SIRT3-IDH2 axis. IDH2 knockout (KO) mice were exposed to a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), to validate IDH2's role in colon cancer development. In vitro, fructose’s effects on SIRT3 expression and IDH2 activity were assessed. Results Fructose-fed WT mice exhibited suppressed AhR signaling, increased oxidative stress, and mitochondrial dysfunction via the SIRT3-IDH2 axis. In human liver datasets, AhR-associated genes and SIRT3-IDH2 expression were reduced in MASLD and cirrhosis. IDH2 KO mice showed heightened DNA damage, colonic tumorigenesis, and mitochondrial and GSH-mediated detoxification disruptions following PhIP exposure. In vitro, fructose reduced SIRT3 expression and IDH2 activity, further supporting its role in promoting colon carcinogenesis. Conclusion Fructose promotes colon carcinogenesis by disrupting mitochondrial function and impairing DNA damage response mechanisms, particularly through SIRT3-IDH2 axis suppression. These findings highlight the critical role of mitochondrial dysfunction in fructose-induced carcinogenesis and suggest the SIRT3-IDH2 axis as a potential therapeutic target.