PROJECT SUMMARY – OVERALL
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a rising cause of cancer mortality.
HCC related to metabolic stress is on the rise, with nonalcoholic steatohepatitis (NASH) rapidly becoming the
dominant etiology. We hypothesize that stress-induced metabolic reprogramming via NRF2 and ATF6
alters, glucose, lipid, and cholesterol metabolism to augment glycolysis and induce mitochondrial
dysfunction through STARD1 and SAB, which collaborates with genetic alterations to accelerate NASH
progression to HCC through a self-sustained downward spiral. Interference with key components of this
network may suppress HCC progression and can yield novel interceptive strategies. Our preliminary data
indicate that interactions between the cytosol and nucleus (AKT;NRF2), the endoplasmic reticulum (ER; ATF6)
and mitochondria (STARD1+SAB) contribute synergistically to NASH-driven HCC. Elimination of any of these
components attenuates HCC and their activation exacerbates HCC progression in murine models. Together, our
outstanding team of investigators will address the pathological significance and mechanisms underlying the
crosstalk between these pathways via 3 projects: Project 1 will interrogate how the newly discovered NRF2-
FBP1 tug-of-war is regulated to support HCC progression. It will identify the first cells in which NRF2 and
AKT are activated to drive FBP1 degradation and the cues that trigger this switch. Lineage tracing will determine
whether NRF2-high HCC directly originates from FBP1-high senescent NASH hepatocytes and the role of diet-
induced DNA damage in hepatocyte senescence and mutagenesis will be elucidated. Project 2 will define how
ATF6 drives HCC in response to metabolic stress. It will uncover the mechanism by which ER stress and the
unfolded protein response transducer ATF6 promotes NASH progression to HCC, likely through NRF2 and FBP1
degradation, the reprogramming of lipid and cholesterol metabolism, and will test whether and how ATF6 ablation
or inhibition abrogate NASH-driven HCC. Project 3 will explore how metabolic stress and cholesterol trigger
mitochondrial dysfunction through STARD1 and SAB to drive HCC. Mitochondrial outer membrane proteins
STARD1 and SAB may contribute to NASH and HCC development through altered cholesterol trafficking and
bile acid synthesis, mitochondrial dysfunction that triggers ROS production, resulting in NRF2 and ATF6
activating oxidative and/or ER stress. This PPG offers an unprecedented opportunity for advanced
understanding of NASH-driven HCC via proximal metabolic regulators and DNA damage controlled by NRF2,
ATF6, and STARD1/SAB. Extensive collaborative interactions and coordinated administrative resources (Core
A), shared use of dietary and transgenic mouse models, metabolic profiling/flux studies (Core 1) and extensive
“omic” and bioinformatic analyses (Core 2) will further enhance collaborations and ensure uniform success
throughout all projects. This P01 offers a unique translational opportunity to define how energy rich diets impact
regulators that promote NASH progression to HCC, generating new preventive and therapeutic strategies.
