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

Authors: PAN, JEONG - Chosun University; AYKIN-BURNS, NUKHET - University Arkansas For Medical Sciences (UAMS); KRAGER, KIMBERLY - University Arkansas For Medical Sciences (UAMS); SHIN, HYO RI - Korea University; LEE, CHAE HWAN - Korea University; Kong, Byungwhi; LEE, JIN - (NCE, CECR)networks Of Centres Of Exellence Of Canada, Centres Of Excellence For Commercilization A; CHOI, KYUNG-CHUL - University Of Ulsan College Of Medicine; KIM, JAE KYEOM - Korea University

Submitted to: Experimental & Molecular Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/20/2025
Publication Date: N/A
Citation: N/A

Interpretive Summary: Fructose-containing sweeteners are widely used (e.g., beverages) and represent ˜30% of total sweeteners consumed in the US. Implications of fructose on public health are still under investigation; multiple studies have focused on the involvement of fructose in metabolic syndromes, however, studies tied to funding from the food industry often fail to demonstrate this relationship. Fructose intake may also play a role in modulating cellular pathways including oxidative stress, which is closely associated with carcinogenesis (causing cancer). Mitochondrial NADP+- dependent isocitrate dehydrogenase (IDH2) enzyme is known to play crucial roles in carcinogenesis. Understanding the mechanistic link between fructose and colon cancer is critical, as it could reveal new insights into the potential carcinogenic effects of high fructose intake and inform strategies for mitigating the risks associated with excessive fructose consumption. In the present study, unbiased multi-omics techniques were used in conjunction with comprehensive bioinformatics analyses to find key molecular interactions responsible for the initiation of colon cancer. Overall, herein, the use of a multi-omics approach allows us to capture the complexity of these molecular interactions, providing a more holistic view of how dietary risk factors can contribute to carcinogenesis.

Technical Abstract: The potential roles of fructose in promoting colon cancer are of growing concern. Fructose consumption has been linked to oxidative stress and mitochondrial dysfunction, yet its specific molecular mechanisms in colon carcinogenesis remain underexplored. 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). 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. 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 studies examined the effects of fructose on SIRT3 expression and IDH2 activity. Fructose-fed WT mice exhibited suppressed Aryl Hydrocarbon Receptor signaling, increased oxidative stress, and mitochondrial dysfunction mediated by the SIRT3-IDH2 axis. IDH2 KO mice showed heightened DNA damage, colonic tumorigenesis, and disruptions in mitochondrial and GSH-mediated detoxification pathways following PhIP exposure. In vitro, fructose reduced SIRT3 expression and IDH2 activity, further supporting its role in promoting colon carcinogenesis. Fructose promotes colon carcinogenesis by disrupting mitochondrial function and impairing DNA damage response mechanisms, particularly through the suppression of the SIRT3-IDH2 axis. These findings highlight the critical role of mitochondrial dysfunction in fructose-induced carcinogenesis and suggest the SIRT3-IDH2 axis as a potential therapeutic target.