Poster #003, Sanford Burnham Prebys Medical Discovery Institute
Elucidating the Role of UBD in Metabolic Dysfunction-Associated Steatohepatitis (MASH)
Mentors: Souradipta Ganguly, PhD and Debanjan Dhar, PhD
Metabolic dysfunction–associated steatohepatitis (MASH) progresses through inflammation,
fibrosis, and hepatocellular injury, and can lead to cirrhosis or hepatocellular carcinoma. Our
previous research has shown that Ubiquitin D (UBD), a stress-inducible ubiquitin-like modifier
that plays a role in the development of chronic liver diseases and cancer, is markedly elevated in
MASH liver tissue, and that suppressing UBD lessens inflammation and fibrosis. However, the
downstream mechanisms responsible for this beneficial effect remain unclear. In this project, we
aimed to identify proteins and pathways regulated by UBD that may contribute to MASH
progression. Using proteomics on liver tissue following acute UBD knockdown, we found
increased levels of two transcription factors: FOXA2, which sustains metabolic homeostasis in
the liver by regulating glucose production and lipid metabolism, and FOXO3, a regulator of
cellular homeostasis and stress responses in the liver through means such as antioxidant response
and autophagy. Because loss of either factor may result in hepatocyte dysfunction, we
investigated whether UBD suppresses FOXA2 and FOXO3 and thereby contributes to MASH
progression. Results from immunohistochemistry and Western blotting assays showed that as
MASH advanced, FOXA2 and FOXO3 protein levels declined while UBD expression rose.
Additionally, when UBD was downregulated, FOXA2 and FOXO3 levels recovered. This
displays an inverse relationship between UBD and FOXA2/FOXO3, suggesting that UBD may
suppress these transcription factors, and that this suppression may be a driver of MASH
pathology. Currently, immunoprecipitation experiments are assessing whether UBD interacts
with FOXA2 to control its stability, and CRISPR/Cas9 knockout of FOXO3 with UBD
downregulation is being used to determine how the loss of these factors affects cellular stress,
lipid buildup, and injury signaling in hepatocytes. Together, our work points to a possible
UBD–FOXA2/FOXO3 regulatory axis as a driver of hepatocyte dysfunction in MASH, and it
presents a promising target for future therapies.