AKR1B1 drives hyperglycemia-induced metabolic reprogramming in MASLD-associated hepatocellular carcinoma
NP Syamprasad,
Siddhi Jain,
Bishal Rajdev,
Samir Ranjan Panda,
Gangasani Jagadeesh Kumar,
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
Affiliations
NP Syamprasad
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Siddhi Jain
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Bishal Rajdev
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Samir Ranjan Panda
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Gangasani Jagadeesh Kumar
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Khaja Moinuddin Shaik
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
P.A. Shantanu
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Veerabhadra Swamy Challa
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Sachin B. Jorvekar
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Roshan M. Borkar
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India
Jayathirtha Rao Vaidya
Fluoro Agro Chemicals Department and AcSIR-Ghaziabad, CSIR-Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad, Telangana, 500007, India
Dinesh Mani Tripathi
Liver Physiology & Vascular Biology Lab, Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, ILBS, D-1, Vasant Kunj, New Delhi, Delhi 110070, India; Corresponding authors. Addresses: National Institute of Pharmaceutical Education and Research, Changsari, Guwahati, Assam, 781101, India. (V.G.M. Naidu) or Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, ILBS, D-1, Vasant Kunj, New Delhi, Delhi 110070, India; (D.M. Tripathi).
V.G.M. Naidu
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam, 781101, India; Corresponding authors. Addresses: National Institute of Pharmaceutical Education and Research, Changsari, Guwahati, Assam, 781101, India. (V.G.M. Naidu) or Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, ILBS, D-1, Vasant Kunj, New Delhi, Delhi 110070, India; (D.M. Tripathi).
Background & Aims: The mechanism behind the progressive pathological alteration in metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH)-associated hepatocellular carcinoma (HCC) is poorly understood. In the present study, we investigated the role of the polyol pathway enzyme AKR1B1 in metabolic switching associated with MASLD/MASH and in the progression of HCC. Methods: AKR1B1 expression was estimated in the tissue and plasma of patients with MASLD/MASH, HCC, and HCC with diabetes mellitus. The role of AKR1B1 in metabolic switching in vitro was assessed through media conditioning, lentiviral transfection, and pharmacological probes. A proteomic and metabolomic approach was applied for the in-depth investigation of metabolic pathways. Preclinically, mice were subjected to a high-fructose diet and diethylnitrosamine to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching characteristic of MASLD-HCC. Results: A significant increase in the expression of AKR1B1 was observed in tissue and plasma samples from patients with MASLD/MASH, HCC, and HCC with diabetes mellitus compared to normal samples. Mechanistically, in vitro assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, the tricarboxylic acid cycle, and lipogenesis to promote hyperglycemia-mediated MASLD and cancer progression. A pathological increase in the expression of AKR1B1 was observed in experimental MASLD-HCC, and expression was positively correlated with high blood glucose levels. High-fructose diet + diethylnitrosamine-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. AKR1B1 inhibition with epalrestat or NARI-29 inhibited cellular metabolism in in vitro and in vivo models. Conclusions: Pathological AKR1B1 modulates hepatic metabolism to promote MASLD-associated hepatocarcinogenesis. Aldose reductase inhibition modulates the glycolytic pathway to prevent precancerous hepatocyte formation. Impact and implications: This research work highlights AKR1B1 as a druggable target in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC), which could provide the basis for the development of new chemotherapeutic agents. Moreover, our results indicate the potential of plasma AKR1B1 levels as a prognostic marker and diagnostic test for MASLD and associated HCC. Additionally, a major observation in this study was that AKR1B1 is associated with the promotion of the Warburg effect in HCC.
