Targeting the TFEB–NUPR1 Axis to treat hepatobiliary manifestations of Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC) is a genetic condition that can cause tumors to grow in many parts of the body. Most research has focused on problems in the brain and kidneys, but the liver and bile ducts (the hepato-biliary system) can also be affected. These issues can include abnormal growth of bile duct cells, cysts, and benign liver tumors. Although these symptoms are part of the gastrointestinal system, they are still poorly understood, and patients currently have very few treatment options. The only available therapy today is a drug that blocks a pathway called mTOR, but this treatment often has side effects and does not work well for liver and bile duct problems. For this reason, we are looking for new, more precise treatment strategies. Our recent research has identified two proteins, TFEB and NUPR1, that work together to control cell growth in the liver. In TSC, TFEB becomes unusually active and increases the levels of NUPR1, which then encourages bile duct cells to multiply and form cyst-like lesions. Importantly, blocking NUPR1 in laboratory models reduces liver cell overgrowth. In this project, we will test whether inhibiting NUPR1 can reduce bile duct abnormalities in a mouse model of TSC. If successful, this work could lead to a new therapeutic approach for liver-related complications in TSC, offering an alternative to current treatments and benefiting both children and adults living with the disease.