Blockade of 11β-hydroxysteroid dehydrogenase type 1 ameliorates metabolic dysfunction-associated steatotic liver disease and fibrosis
Hwan Ma,
Guo-Yan Sui,
Jeong-Su Park,
Feng Wang,
Yuanqiang Ma,
Dong-Su Shin,
Nodir Rustamov,
Jun Sung Jang,
Soo Im Chang,
Jin Lee,
Yoon Seok Roh
Affiliations
Hwan Ma
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea
Guo-Yan Sui
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea
Jeong-Su Park
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea
Feng Wang
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea
Yuanqiang Ma
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea
Dong-Su Shin
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea
Nodir Rustamov
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea
Jun Sung Jang
Ahngook Pharmaceutical, Seoul, South Korea
Soo Im Chang
Ahngook Pharmaceutical, Seoul, South Korea
Jin Lee
Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA; Corresponding author. Department of Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA.
Yoon Seok Roh
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea; Corresponding author. Department of Pharmacy, Chungbuk National University College of Pharmacy, 194-21 Osong-Saeng-Myung-1 Ro, Cheong-Ju, 28160, South Korea.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key enzyme involved in the conversion of cortisone to active cortisol in the liver. Elevated cortisol levels can trigger oxidative stress, inflammation, and hepatocyte damage, highlighting the importance of 11β-HSD1 inhibition as a potential therapeutic approach. This study aimed to explore the effects of INU-101, an inhibitor of 11β-HSD1, on the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Our findings demonstrated that INU-101 effectively mitigated cortisol-induced lipid accumulation, reactive oxygen species generation, and hepatocyte apoptosis. Furthermore, 11β-HSD1 inhibition suppressed hepatic stellate cell activation by modulating β-catenin and phosphorylated SMAD2/3. INU-101 administration significantly reduced hepatic lipid accumulation and liver fibrosis in mice fed fast-food diet. This study suggests that INU-101 holds promise as a clinical candidate for treating MASLD and fibrosis, offering potential therapeutic benefits by targeting the intricate processes involving 11β-HSD1 and cortisol regulation in the liver.
