Theses and Dissertations

Date of Award

8-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry and Molecular Biology

First Advisor

Sheema Khan

Second Advisor

Subhash Chauhan

Third Advisor

Yonghong Zhang

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD), encompassing stages from steatosis (MASLD) to steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma (HCC), is the most prevalent chronic liver disease worldwide, yet molecular markers of progression remain limited. The G protein–coupled estrogen receptor (GPER), a non-genomic estrogen receptor with metabolic and anti-inflammatory roles, emerges as a candidate regulator in hepatic pathophysiology. In this Dissertation thesis, we have delineated for the first time clinicopathological assessment of liver biopsies across MASLD stages revealing a robust inverse correlation between GPER expression and disease severity. Higher GPER levels in early MASLD associated with favorable metabolic and biochemical profiles, whereas advanced disease stages exhibited marked downregulation, particularly in the presence of elevated transaminases, lipid dysregulation, or cholestatic stress. GPER regulation appeared sex-independent, supporting its potential as a universal biomarker. Additionally, we have explored GPER’s mechanistic role in HCC through pharmacologic activation (G1) and antagonism (G36). In multiple HCC cell lines, G1 impaired proliferation, migration, and spheroid growth, and synergistically enhanced Sorafenib cytotoxicity. Mechanistically, GPER activation disrupted autophagic flux via downregulation of Beclin1 and ATG proteins, suppressed pro-survival transcriptional programs (YAP, TEAD, CHOP), and activated the KEAP1–NRF2 antioxidant axis, upregulating detoxifying enzymes. Despite this antioxidant induction, autophagy blockade predominated, tipping the balance toward cell death. Antagonist reversal confirmed GPER-specific effects, and baseline expression predicted responsiveness to activation. Collectively, these findings position GPER as both a stage-specific biomarker for MASLD progression and a therapeutic target in HCC. Its dual roles in early metabolic protection and in promoting tumor suppression upon activation, offer translational potential for disease stratification and targeted therapy development in metabolic liver disease and cancer.

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Copyright 2025 Hossain Ahmed. All Rights Reserved. https://proquest.com/docview/3254044484

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