Novel drug discovery from the perspective of iron metabolism and ferroptosis regulation in liver diseases

Abstract

The global rise in liver disease imposes a major healthcare challenge, underscoring the need for innovative treatments. Liver diseases are complex and progress over time, often requiring long-term and targeted therapeutic interventions. Iron, a vital mineral in the human body, plays a crucial role in multiple physiological processes. However, due to its redox-active properties, iron can also act as a double-edged sword, potentially generating harmful free radicals that damage cellular structures. This thesis summarizes our research into new treatments for liver diseases by targeting iron metabolism and ferroptosis (a newly defined iron-dependent type of cell death) by taking advantage of the dual-sword nature of iron.
The introductory chapter provides an overview of liver disease pathogenesis, hepatocyte injury, iron metabolism, and ferroptosis, highlighting recent advancements and gaps in the field. The following section offers a systematic review of iron metabolism in non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC), summarizing disrupted iron regulation and identifying potential therapeutic targets across clinical and experimental settings.
Preventing iron overload and ferroptosis emerges as an effective strategy to reduce hepatocyte damage and restore liver function. One critical regulator, the hepatic Aryl hydrocarbon receptor (AhR), is markedly upregulated in NAFLD and NASH patients. To investigate this, we developed a NASH mouse model using an L-amino acid-defined, high-fat diet that effectively simulates hepatocyte damage, iron dysregulation, and hepatic ferroptosis. Analysis of liver tissues and hepatocyte models revealed that AhR was significantly upregulated in NASH. Inhibition of AhR with the antagonist CH223191 (5 mg/kg) led to substantial improvements in liver injury, inflammation, lipid buildup, and collagen deposition—comparable to, or exceeding, those seen with the iron chelator deferoxamine (DFO, 100 mg/kg). Our findings indicate that AhR inhibition reduces hepatic iron overload and ferroptosis via the Pten/Akt/β-catenin pathway, positioning AhR as a promising therapeutic target for NASH. Detailed findings on these mechanisms are presented in Chapter 4.
Building on the discovery of ferroptosis and the "iron-addict" nature of cancer cells, we further investigated potential therapeutic strategies for HCC. In Chapter 5, we examine the anti-tumor potential of a novel oridonin-derived compound, XD, in HCC. XD exhibited effective inhibition of HCC, surpassing positive control drugs in efficacy. Importantly, XD’s cytotoxic effects were linked to ferroptosis induction. Mechanistic studies suggested that XD inhibits G6PD and PGD enzymes, leading to downregulation of ferroptosis regulators FSP1 and DHODH, ultimately triggering ferroptotic cell death. Molecular docking simulations indicated XD's binding potential to G6PD and PGD. Additionally, XD injection (10, 20 mg/kg) resulted in dose-dependent suppression of liver tumor growth in mice. Collectively, these findings position XD as a promising candidate for anti-tumor therapy and highlight the novel regulatory role of the G6PD/PGD/FSP1/DHODH axis in ferroptosis sensitivity.
In summary, this work underscores the critical roles of iron metabolism and ferroptosis in liver diseases, suggesting potential treatments for both NASH and HCC by modulating iron and ferroptosis. Specifically, AhR inhibition may protect hepatocytes from iron toxicity in NASH, while XD-induced ferroptosis offers anti-tumor strategy against HCC. These insights provide a foundation for potential therapies, offering new perspectives on disease progression and therapeutic innovation in liver disease.

Date of Award	Mar 2025
Original language	English
Awarding Institution	University of Nottingham
Supervisor	Cheng Heng Pang (Supervisor), Guoyu Pan (Supervisor), Zheying Zhu (Supervisor) & Richard Rankin (Supervisor)