# Metabolic Concepts of Sodium-Glucose Cotransporter 2 Inhibitors-Based Therapies Against Hepatocarcinogenesis and Therapy Resistance in Hepatocellular Carcinoma

## TL;DR

This review explores how SGLT2 inhibitors, used for diabetes, might help treat liver cancer by targeting metabolic pathways and reducing therapy resistance.

## Contribution

The paper highlights the potential of SGLT2 inhibitors in HCC treatment through metabolic reprogramming and immune modulation.

## Key findings

- SGLT2 inhibitors may reduce HCC progression and therapy resistance via multiple mechanisms.
- Upregulated SGLT2 expression is linked to hepatocarcinogenesis and therapy resistance.
- Combining SGLT2 inhibitors with other therapies could enhance anti-cancer effects in HCC.

## Abstract

The prevalence of hepatocellular carcinoma (HCC) has increased in recent years and resulted in many deaths, which necessitates new therapeutic solutions. The pathogenesis of HCC is associated with uncontrolled metabolic modulation and resistance to therapy. As diabetic carcinogenesis accelerates HCC progression, proper evaluation of anti-diabetic drugs to attenuate HCC is important. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors that suppress renal SGLT2 are beneficial for treating diabetes, chronic kidney diseases, and heart failure, the use of SGLT2 inhibitors for treating HCC remains unclear. In this review article, some oncotargets involved in metabolic reprogramming, including glucose metabolism, Wnt/β-catenin, and hypoxia-inducible factor-1 alpha signaling, and the tumor microenvironment of HCC are briefly highlighted. Moreover, upregulated SGLT2 expression may be associated with hepatocarcinogenesis and therapy resistance, whereas the incorporation of SGLT2 inhibitors into combination therapies effectively attenuates HCC progression, metastasis, and therapy resistance through multiple mechanisms. Notably, how SGLT2 inhibitors modulate immune responses to cancer vaccines against HCC is highly appreciated and requires further evaluation. Thus, the clinical application of SGLT2 inhibitors in HCC and therapy resistance provides a promising direction for therapeutic strategies.