My research: a PhD student explains
Odysseia Savvoulidou
The purpose of the thesis is to explore the role of endogenous hydrogen sulfide (H₂S) signaling in the development and progression of liver disease.
What is the title of your thesis?
Hydrogen Sulfide Signaling in Liver Disease: From Metabolic Dysfunction to Therapeutic Targets.
At which department and/or research unit did you complete your PhD?
Department of Molecular Medicine, Cardiovascular and Renal Research.
Who was your principal supervisor?
Assist. Prof. Maria Peleli and Prof. Daniel F. J. Ketelhuth, SDU.
What question did you aim to answer with your thesis?
The purpose of my PhD thesis was to explore the role of endogenous hydrogen sulfide (H₂S) signaling in the development and progression of liver disease, more specifically metabolic dysfunction-associated steatotic liver disease (MASLD), and to gain insight into whether modulation of H₂S biosynthesis could represent a therapeutic strategy to combat it.
In this context, I investigated the importance of H₂S-producing enzymes in maintaining hepatic and vascular homeostasis during MASLD and determined whether enhancing or restoring H₂S signaling can protect against hepatic metabolic dysfunction, inflammation and fibrosis, as well as preserve liver sinusoidal endothelial cell (LSEC) function.
What did you find?
My studies demonstrated that endogenous H₂S signaling plays an important role in maintaining hepatic and vascular homeostasis during MASLD. Our findings showed that the two major H₂S-producing enzymes, 3-mercaptopyruvate sulfur transferase (MPST) and cystathionine γ-lyase (CTH), have some distinct but also complementary roles in disease progression.
Hepatocyte-specific overexpression of MPST increased hepatic H₂S production, improved hepatic lipid metabolism, and reduced inflammation, macrophage infiltration, and fibrosis in experimental MASLD. Hence, I found that CTH-derived H₂S is important for maintaining liver LSEC homeostasis, as impairment of the CTH/H₂S pathway aggravated lipotoxicity-induced endothelial dysfunction, whereas restoration of H₂S bioavailability partially improved endothelial integrity and angiogenic capacity.
Overall, my findings support a protective role of endogenous H₂S signaling in MASLD and suggested that targeting H₂S-producing pathways may represent a potential therapeutic strategy to attenuate hepatic and vascular dysfunction and disease progression.
How did you do it?
My PhD project combined experimental approaches using animal models and laboratory cell systems. In animal studies, diet-induced MASLD was established in mice, and a liver-targeted viral vector was used to increase MPST expression specifically in the liver, allowing its effects to be investigated both before and after disease development.
Hepatic metabolism, lipid composition, inflammation, and fibrosis were assessed using molecular, biochemical, histological, and lipidomic analyses. For the role of CTH-derived H₂S in LSEC function, I used human and primary mouse LSECs exposed to lipids to mimic lipotoxic conditions, together with pharmacological inhibition and genetic deletion of CTH. H₂S donors were also used to determine whether restoring H₂S availability could improve endothelial dysfunction.
How can your research be applied (in the clinic, society, etc.)?
The results of my research provide new insight into how altered H₂S signaling contributes to MASLD and identified MPST and CTH as potential therapeutic targets that, when modulated, may help prevent or slow disease progression.
Based on this therapeutic concept, we have filed a patent application, and our group will continue working to further develop this approach, with the ultimate goal of reaching clinical studies. If successful, this could contribute to new treatment options and help reduce the growing clinical and societal burden of MASLD.