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Last update 08 May 2025

HADHB

Last update 08 May 2025

Basic Info

Synonyms

3-ketoacyl-CoA thiolase, Acetyl-CoA acyltransferase, Beta-ketothiolase

+ [5]

Introduction

Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:29915090, PubMed:30850536, PubMed:8135828). The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (PubMed:30850536). Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities, while the trifunctional enzyme subunit beta/HADHB described here bears the 3-ketoacyl-CoA thiolase activity (PubMed:29915090, PubMed:30850536, PubMed:8135828).

Drugs associated with HADHB

Ninerafaxstat

Target

HADHB

Mechanism

HADHB inhibitors [+1]

Active Org.

Imbria Pharmaceuticals, Inc.

Originator Org.

Imbria Pharmaceuticals, Inc.

Active Indication

Hypertrophic Cardiomyopathy without Obstruction [+6]

Inactive Indication

Refractory angina

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with HADHB

NCT04306237

/ SuspendedPhase 2

A Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of IMB-1018972 in Patients With Refractory Angina

The objectives of the study are to assess the safety, tolerability, and potential efficacy of IMB-1018972 on patients with refractory angina. Study will assess functional capacity employing a modified Bruce Protocol treadmill ETT, patient reports of angina symptoms via an electronic diary, and activity using an accelerometer.

Start Date01 Nov 2023

Sponsor / Collaborator

Imbria Pharmaceuticals, Inc.

NCT04826185

/ CompletedPhase 2

A Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of IMB-1018972 in Patients With Non-obstructive Hypertrophic Cardiomyopathy

The purpose of this study is to assess the safety, tolerability, and potential efficacy of IMB-1018972 in patients with non-obstructive HCM.

Start Date14 Jun 2021

Sponsor / Collaborator

Imbria Pharmaceuticals, Inc.

NCT04826172

/ CompletedPhase 2

A Randomized, Double-Blind, Placebo-Controlled, Exploratory Study on the Safety, Tolerability, and Pharmacodynamics of IMB-1018972 in Subjects With Angina Due to Obstructive Coronary Artery Disease

The purpose of this study is to assess the safety and tolerability of IMB-1018972 in subjects with obstructive CAD and inducible ischemia.

Start Date23 Apr 2021

Sponsor / Collaborator

Imbria Pharmaceuticals, Inc.

100 Clinical Results associated with HADHB

100 Translational Medicine associated with HADHB

0 Patents (Medical) associated with HADHB

182

Literatures (Medical) associated with HADHB

01 May 2025·Molecular Carcinogenesis

The Role of HADHB in Mitochondrial Fatty Acid Metabolism During Initiation of Metastasis in ccRCC

Article

Author: Chen, Guijuan ; Dong, Ping ; Gan, Weidong ; Yang, Lei ; Li, Dongmei ; Ding, Yibing ; Ma, Wenliang ; Chen, Yi ; Li, Xin ; Wu, Mengmeng ; Ding, Weidong ; Zhang, Luqing

ABSTRACTThe initiation and progression of clear cell renal cell carcinoma (ccRCC) are closely linked to significant metabolic alterations. Specifically, lipid metabolism alterations and their association with the high invasiveness in ccRCC require further investigation. After conducting RNA‐sequencing (RNA‐seq), we discovered that Hydroxyacyl‐CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta (HADHB) was significantly downregulated in the highly invasive ccRCC cell line. It was found that the expression of HADHB in ccRCC tumor tissues was lower than that in paracancer tissues, which is associated with poor patient prognosis. Subsequently, we confirmed that highly invasive ccRCC exhibited an increased lipid accumulation due to the suppression of mitochondrial fatty acid transport and enhanced conversion of fatty acids to triglycerides within cancer cells. Specifically, the downregulation of HADHB inhibited mitochondrial fatty acid β‐oxidation (FAO) in cancer cells, leading to partial impairment of mitochondrial function and decreased ATP production. However, this trade‐off involving the reduction of a high‐yield ATP production conferred an advantage by reducing reactive oxygen species (ROS) generation within cancer cells, thereby protecting them from oxidative stress and enhancing their invasive potential. Furthermore, the downregulation of HADHB promoted epithelial−mesenchymal transition (EMT) and angiogenesis in cancer cells, accelerating the progression of ccRCC and endowing ccRCC cells with metastatic capabilities.

01 Feb 2025·Toxicology

Effective analysis of thyroid toxicity and mechanisms of acetyltributyl citrate using network toxicology, molecular docking, and machine learning strategies

Article

Author: Peng, Qingping ; Liu, Huan ; Fu, Bowen ; Lan, Yujian

The growing prevalence of environmental pollutants has raised concerns about their potential role in thyroid dysfunction and related disorders. Previous research suggests that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect thyroid health, yet the precise mechanisms remain poorly understood. The objective of this study was to elucidate the complex effects of acetyl tributyl citrate (ATBC) on the thyroid gland and to clarify the potential molecular mechanisms by which environmental pollutants influence the disease process. Through an exhaustive exploration of databases such as ChEMBL, STITCH, and GEO, we identified a comprehensive list of 19 potential targets closely associated with ATBC and the thyroid gland. After rigorous screening using the STRING platform and Cytoscape software, we narrowed this list to 15 candidate targets, ultimately identifying five core targets: CBX5, HADHB, TRIM33, TP53, and CUL4A, utilizing three well-established machine learning methods. In-depth Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses conducted in the DAVID database revealed that the primary pathways through which ATBC affects the thyroid gland involve key signaling cascades, including the FoxO signaling pathway and metabolic pathways such as fatty acid metabolism. Furthermore, molecular docking simulations using Molecular Operating Environment software confirmed strong binding interactions between ATBC and these core targets, enhancing our understanding of their interactions. Overall, our findings provide a theoretical framework for comprehending the intricate molecular mechanisms underlying ATBC's effects on thyroid damage and pave the way for the development of preventive and therapeutic strategies against thyroid disorders caused by exposure to ATBC-containing plastics or overexposure to ATBC.

02 Jan 2025·Cancer Research

TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis

Article

Author: Shen, Kangjie ; Gu, Jianying ; Wei, Chuanyuan ; Gao, Zixu ; Yang, Yang ; Luo, Zucheng ; Yang, Yanwen ; Wang, Lu ; Zheng, Shaoluan ; Zhang, Tianyi ; Zhu, Yu ; Wei, Chenlu ; Ming, Ren ; Ding, Yiteng ; Li, Yinlam ; Xuan, Jiangying ; Hu, Qianrong ; Li, Jianrui

AbstractMetabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. In this study, we identified that tectonic family member 1 (TCTN1) promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo and induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor epithelial–mesenchymal transition and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma.Significance: TCTN1 activates fatty acid oxidation to induce melanoma mesenchymal phenotype switching and invasion by promoting the binding of the subunits of MTP, which can be targeted with fluprostenol to inhibit melanoma metastasis.

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HADHB

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