Effects of SGLT2 Inhibitor on the Progression and Metabolisms in Metabolism-Associated Liver Cancer: Multi-Omics Analysis of Metabolomics/Proteomics

Background and Aims: Metabolic reprogramming is associated with the progression of metabolism-associated liver cancer (MALC). A sodium-glucose cotransporter 2 inhibitor (SGLT2i) affects various metabolisms. We aimed to investigate the effect of SGLT2i on the progression and metabolisms of MALC by metabolomics/proteomics.
Methods: Study 1. Steatohepatitis-inducing high-fat diet mice were treated with SGLT2i (ipragliflozin; n=6) or methylcellulose (n=6) for 36 weeks. Study 2. The levels of metabolites and metabolic enzymes were evaluated by metabolomics and proteomics in Hep3B cells 48 hours after treatment with SGLT2i (canagliflozin 10μM; n=5) or dimethyl sulfoxide (n=5).
Results: Study 1. The number and volume of MALC were significantly suppressed in the SGLT2i group compared to the control group (5.1 vs. 2.3/liver; P<0.01, 6.2 vs. 3.2 mm³; P<0.01). Study 2. In metabolomics, acetylcarnitine and butyrylcarnicine were significantly up-regulated in the SGLT2i group compared to the control group. In proteomics, there was a significant suppression in the expression of ATP synthase F1 subunit alpha (297 vs. 251 fmol/protein; P=0.0183) and acetyl-coenzyme A acyltransferase 1 (35.5 vs. 30.4 fmol/protein; P=0.0206) in the SLGT2i group compared to the control group.
Conclusions: SGLT2i suppressed the progression of MALC in a mouse model. The multi-omics analysis revealed that SGLT2i regulated the mitochondrial electron transport system and beta-oxidation. Thus, SGLT2i may suppress MALC through the regulation of fatty acid metabolism.