Molecular Pathway Dysregulation in Chronic Liver Disease: Metabolic and Mechanotransductive Drivers of Hepatic Pathophysiology

Authors

Samantha Harvat, University of Nebraska-LincolnFollow

First Advisor

Srivatsan Kidambi

Committee Members

Rajib Saha, Vitali Alexandrov

Date of this Version

12-2025

Document Type

Thesis

Citation

A thesis presented to the faculty of the Graduate College at the University of Nebraska in partial fulfillment of requirements for the degree of Master of Science

Major: Chemical Engineering

Under the supervision of Professor Srivatsan Kidambi

Lincoln, Nebraska, December 2025

Comments

Copyright 2025, Samantha Harvat. Used by permission

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD) represents a rapidly growing cause of chronic liver injury, yet the molecular interactions linking metabolic stress, inflammation, fibrosis, and hepatocellular carcinoma (HCC) remain incompletely defined. This thesis integrates transcriptomic analyses across multiple GEO datasets to identify coordinated metabolic, inflammatory, and mechanotransductive pathways that collectively drive disease progression.

Analysis of human liver biopsy datasets (GSE126848 and GSE89632) revealed consistent suppression of glycolysis, β-oxidation, and oxidative phosphorylation across MASLD and MASH samples, accompanied by modest compensatory TCA cycle activation. These alterations reflect impaired metabolic flexibility, mitochondrial stress, and increased ROS susceptibility. Concurrently, cytokine-network enrichment demonstrated activation of IL-6, TNF, and chemokine pathways, highlighting a metabolic–inflammatory feedback loop driven by oxidative stress and immune engagement.

To examine how these biochemical disturbances interface with liver tissue mechanics, additional datasets (GSE25097, GSE6764, GSE14323, GSE36376) were analyzed for mechanotransductive signatures. Results showed consistent upregulation of YAP1, CTGF, and CYR61, reduced expression of Hippo inhibitory regulators, and increased COL1A1, COL3A1, FN1, ACTA2, and LOX expression—indicating progressive ECM deposition, crosslinking, and stiffness. These findings support a model in which metabolic stress and inflammation promote cytoskeletal tension and YAP/TAZ activation, while YAP/TAZ-driven matrix remodeling reinforces tissue stiffness, sustaining fibrosis independent of upstream insults.

Together, these results highlight a unified mechanometabolic framework in which metabolic dysfunction, inflammatory activation, and mechanical remodeling operate as interdependent drivers of chronic liver disease. This integrated model identifies combined metabolic–mechanotransductive therapeutic strategies as promising avenues for interrupting the feedback loops that underlie fibrosis progression and HCC development.

Advisor: Srivatsan Kidambi