Cell-specific Functions for PFKFB3 in Metabolic Liver Disease

Health challenge: Chronic liver disease (CLD) is a significant global health concern that is associated with a reduced health-related quality of life. >1.5 billion people worldwide are at risk of developing cirrhosis or liver cancer, both of which carry a significant risk of early mortality. In the UK, CLD represents 2.5% of all deaths and is linked with social deprivation, with premature deaths from CLD in the most deprived areas being 4-fold higher than in the most affluent regions. Currently, 90% of CLD cases are due to alcohol, obesity, and viral hepatitis, but with 63% of UK adults obese or overweight, obesity-driven CLD is predicted to be the main cause of end-stage liver disease and liver transplant within a decade. Metabolic dysfunction associated steatohepatitis (MASH) is the name for advanced obesity-driven CLD and is defined by accumulation of liver fat (steatosis), inflammation and scar tissue deposition (fibrosis). Liver fibrosis is the strongest predictor of disease progression and poor outcome. Currently, Resmetirom, a thyroid hormone receptor agonist, is the only clinically proven drug to suppress fibrosis, however the anti-fibrotic efficacy was reported at 26% vs 14% placebo and long-term effects are unknown. Hence there remains the urgent need to identify additional drug targets. Importantly, studies with Resmetirom and other metabolic modulators (e.g. PPAR agonists) offer new hope that targeting dysregulated metabolic pathways in MASH can deliver effective treatments. We discovered that a metabolic protein called PFKFB3, which increases a cell’s use of glucose (sugar) to fuel its biological activities, is increased in CLD and MASH. In CLD, PFKFB3 in hepatocytes (functional liver cells), caused them to change their behaviour and release factors that promote inflammation and fibrosis. Whilst PFKFB3 in specialised immune cells called macrophages, further amplified these responses, suggesting that PFKFB3 activities in hepatocytes and macrophages establish a pro-fibrotic communication between each other and scar-forming cells (myofibroblasts), to promote liver fibrosis. We hypothesise that inhibiting PFKFB3 activity will metabolically rebalance these cells in MASH and limit liver fibrosis. Aims 1-2 will assess if drugs that inhibit PFKFB3 in human liver slices (thin slices of tissue cultured in the lab) and pre-clinical MASH models limit liver steatosis, inflammation, or fibrosis. We will examine how PFKFB3 alters hepatocyte, macrophage and/or scar-forming cell biology in MASH using genetic models where PFKFB3 is deleted in these cells, to better understand the disease biology and identify new drug targets. Liver cancer is a devastating disease with a desperately poor prognosis and is the 2nd most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common primary liver cancer and MASH patients have a higher risk of developing HCC. Antibody therapies called “immunotherapy” are the best available treatment for unresectable HCC, and extend life by ~8 months, however efficacy is limited to only a minority of patients. Aim 3 will determine if targeting PFKFB3 in MASH limits progression of MASH to MASH-HCC and explore whether PFKFB3-inhibitors alone or in combination with immunotherapy, halt cancer growth once MASH-HCC is established. Potential applications and benefits: completing this project will (i) reveal how PFKFB3 signalling in different cell types contribute to MASH/MASH-HCC; (ii) discover new mechanistic biology of broad interest to scientists in the fields of CLD, fibrosis and cancer; (iii) ascertain if PFKFB3 inhibitors can be effective in suppressing MASH and/or MASH-HCC.