BD1-biased BET inhibition attenuates TXNIP-associated inflammation in diabetic MASH PMID: 42475798

GLP-1 and Obesity Research

2026-08-18

BD1-biased BET inhibition attenuates TXNIP-associated inflammation in diabetic MASH

Tissue Cell. 2026 Jul 16;104(Pt 1):103797. doi: 10.1016/j.tice.2026.103797.

Rabab S Hamad ¹ , Sameh Saber ² , Elsayed A Elmorsy ³ , Maha M Amer ⁴ , Mohamed A M Ali ⁵ , Hanan Eissa ⁶ , Alshaimaa A Farrag ⁷ , Norhan Ahmed AbuoHashish ⁸ , Shereen Hamed ⁹ , Mahmoud A Abdelaziz ¹⁰ , Adel I Alalawy ¹¹ , Alaa Muqbil Alsirhani ¹² , Aljazi Abdullah AlRashidi ¹³ , Mona I Shahin ¹⁴ , Danah M Algarallah ¹⁵ , Rasha Elmowafy ¹⁶ , Ahmed Abdel-Monem Elmetwally ¹⁷ , Ahmed Shata ¹⁸ , Mohamed A S Abd Elzaher ¹⁹ , Mohamed R Abdel-Hamed ²⁰

Affiliations

1. Biological Sciences Department, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia. Electronic address: [email protected].
2. Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: [email protected].
3. Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah 52571, Saudi Arabia; Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
4. Department of Anatomy and Histology, College of Medicine, Qassim University, Buraidah 52571, Saudi Arabia; Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Electronic address: [email protected].
5. Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia. Electronic address: [email protected].
6. Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: [email protected].
7. Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt. Electronic address: [email protected].
8. Pharmacology Department, Faculty of Medicine, Tanta University, Egypt. Electronic address: [email protected].
9. Department of Medical Histology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Faculty of Health Science Technology, Mansoura National University, Gamasa, Egypt. Electronic address: [email protected].
10. Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia. Electronic address: [email protected].
11. Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia. Electronic address: [email protected].
12. Department of Chemistry, College of Science, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia. Electronic address: [email protected].
13. Department of Chemistry, College of Science, University of Ha'il, Ha'il 81451, Saudi Arabia. Electronic address: [email protected].
14. Department of Biology, Faculty of Tymaa, Tabuk University, Tymaa 71491, Saudi Arabia. Electronic address: [email protected].
15. Laboratory-Clinical Biochemistry, King Khalid Hospital, Tabuk, Saudi Arabia. Electronic address: [email protected].
16. Medical Biochemistry and Molecular Biology Department, faculty of Medicine, Mansoura University, Egypt; Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Horus University, Egypt. Electronic address: [email protected].
17. Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
18. Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
19. Department of Medical Laboratories, Ain Shams Specialized Hospital, Ain Shams University, Cairo, Egypt. Electronic address: [email protected].
20. Department of Anatomy and Histology, College of Medicine, Qassim University, Buraidah 52571, Saudi Arabia; Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Electronic address: [email protected].

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive Liver Disease driven by metabolic stress, inflammation, and fibrosis, with limited effective therapies. Thioredoxin-interacting protein (TXNIP) links hyperglycemia and oxidative stress to NLRP3 inflammasome activation, but the epigenetic mechanisms sustaining TXNIP induction in diabetic MASH remain unclear. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader that promotes inflammatory transcription through chromatin engagement. Here, we examined whether BRD4-associated regulation of TXNIP contributes to diabetic MASH and evaluated LT052, a BD1-biased BET bromodomain inhibitor with preferential BRD4 BD1 activity, in a streptozotocin-accelerated dietary rat model. Diabetic MASH caused severe steatohepatitis, fibrosis, Insulin Resistance, oxidative stress, NF-κB activation, TXNIP induction, and NLRP3 inflammasome activation. These changes were accompanied by increased BRD4 occupancy at the TXNIP promoter and elevated total hepatic histone H3 acetylation (Ac-H3K9). LT052 markedly improved liver histopathology, metabolic control, redox balance, and inflammatory outcomes, while reducing TXNIP expression, inflammasome activation, and downstream pyroptotic signaling. Mechanistically, LT052 reduced BRD4 occupancy at the TXNIP promoter and decreased total hepatic Ac-H3K9 without altering total BRD4 expression or nuclear BRD4 immunostaining, consistent with reduced BRD4-associated promoter engagement rather than altered BRD4 abundance or localization. Integrated analyses showed broad, dose-dependent improvement across MASH-relevant endpoints. These findings support further investigation of BD1-biased BET inhibition with LT052 as a therapeutic strategy for diabetic MASH.

Keywords

BD1-biased BET inhibition; Diabetic MASH; Hepatic inflammation; Insulin resistance; TXNIP/NLRP3 inflammasome.