The MASLD-inflammasome axis in inflammatory disease and tumor development

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as NAFLD, has an estimated prevalence around 25-30% of the world’s population. Evidence now shows that MASLD is not confined to the liver, much to the contrary, it is actually a multi-system metabolic and inflammatory disease that increases the risk of several extra-hepatic diseases and cancers. A key inflammatory pathway is the activation of the inflammasome. The inflammasome is a multi-protein complex that assembles in multiple cell types in response to a plethora of pathogen- and host-derived signals. Activation of the inflammasome typically leads to inflammatory cytokine production and cell death by pyroptosis, which is also inflammatory. Our preliminary data shows that the inflammasome complex, in particular the absent in melanoma 2 (AIM2) inflammasome, is activated during MASLD-associated hepatocellular carcinoma (HCC) development. We also provide evidence of inflammasome activation in mice with lung cancer and in the colon of mice with MASLD. Therefore, based on the current literature reporting the multisystemic nature of MASLD and our own preliminary data, we hypothesize that MASLD triggers systemic inflammasome activation which in turn may exacerbate not only HCC but also extrahepatic inflammatory disease and tumor. To test this hypothesis, we propose three main aims: 1. Define the mechanisms whereby AIM2 inflammasome affects the progression from MASLD to HCC. 2. Assess whether the inflammasome links MASLD and colonic disease: CRC, colonic adenomas and IBD. 3. Evaluate the impact of MASLD on non-gastrointestinal tumor development. In Aim 1, we will employ a diet-induced model to interrogate the importance of the AIM2 inflammasome in the progression from MASLD to HCC. We will also perform a prospective study in human patients to determine whether patients with MASLD have systemic evidences of inflammasome activation and whether this correlates with the severity of the disease or the occurrence of HCC. In Aim 2, we will first employ preclinical models of colorectal cancer (CRC), colonic adenomas and inflammatory bowel disease, including a humanized mouse model of CRC to determine whether the presence of MASLD affects systemic inflammasome activation, the tumor microenvironment and/or aggravates CRC growth. We will also analyze the inflammasome status in blood and colonic mucosa of patients with adenomatous polyps in comparison with CRC patients and healthy controls. Last, in Aim 3 we will utilize a mouse model of lung cancer (as example of non-gastrointestinal tumor that is highly associated with inflammation) to interrogate whether MASLD-induced inflammasome activation aggravates non-gastrointestinal tumor development.