AKR1B1 drives hyperglycemia-induced metabolic reprogramming in MASLD-associated hepatocellular carcinoma
Syamprasad NP, Siddhi Jain, Bishal Rajdev, Samir Ranjan Panda, Jagadeesh Kumar Gangasani, Khaja Moinuddin Shaik, P. A. Shantanu, Veerabhadra Swamy Challa, Sachin B. Jorvekar, Roshan M. Borkar, Jayathirtha Rao Vaidya, Dinesh Mani Tripathi, V.G.M. Naidu
Abstract
Background & AimsThe mechanism behind the progressive pathological alteration in MASLD/MASH-associated HCC is poorly understood. In the present study, we have investigated the role of polyol pathway enzyme, AKR1B1 in metabolic switching associated with MASLD/MASH and in the progression of HCC.MethodsThe expression of AKR1B1 in tissue and plasma of patients with MASLD/MASH, HCC, and HCC with diabetes mellitus were estimated. The role of AKR1B1 in metabolic switching in vitro was assessed through media conditioning, lentiviral transfection, and pharmacological probes. The proteomic and metabolomic approach was applied for the in-depth investigation of the metabolic pathway. Preclinically, a high fructose diet (HFrD) and diethyl nitrosamine (DEN) induced mouse model was developed to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching in the pathobiology of MASLD-HCC.ResultsA significant increase in the expression of AKR1B1 was observed in MASLD/MASH, HCC, and HCC-DM tissue and plasma samples compared to normal samples. Mechanistically, in vitro, assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, TCA cycle, and lipogenesis to promote hyperglycemia-mediated MASLD and cancer progression. A pathologically increased expression of AKR1B1 was observed in experimental MASLD-HCC, and expression was positively correlated with high blood glucose levels. HFrD+DEN-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. However, AKR1B1 inhibition with EPS or NARI-29 has inhibited cellular metabolism in vitro and in vivo models.ConclusionsPathological AKR1B1 modulates hepatic metabolism to promote MASLD-associated hepato-carcinogenesis. Aldose reductase inhibition modulates the glycolytic pathway to prevent pre-cancerous hepatocyte formation.Impact & ImplicationsThe research work vitalizes AKR1B1 as a druggable target in MASH/MASLD and HCC, which will provide a base for developing new chemotherapeutic agents. Moreover, the study implicates the use of AKR1B1 levels in plasma as a prognostic marker and diagnostic test for MASLD and associated HCC. Additionally, the major observation in the study was that AKR1B1 is associated with the promotion of the Warburg effect in HCC.