Liver cancer including hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. However, HCC is refractory to almost all current anti-cancer therapies. Nonalcoholic fatty liver disease (NAFLD) is the fastest growing cause of HCC, but the mechanisms governing the progression from NAFLD to NAFLD-HCC remain unclear. Kupffer cells (KCs), the resident macrophages of the liver, are proposed to drive NAFLD-HCC development. However, we have previously shown that KCs are gradually lost from the liver as NAFLD progresses. Moreover, an almost complete absence of KCs is observed in NAFLD-HCC, while mice lacking KCs show an accelerated progression to NAFLD-HCC. We therefore hypothesize that KCs are protective in the setting of NAFLD-HCC and that by manipulating the interactions between KCs and other liver cells, we could promote KC development/maintenance and prevent or slow NAFLD-HCC development. With “ProteKCt”, we aim to determine the precise roles of KCs in driving the progression to NAFLD-HCC in mice and humans. We will utilise state-of-the-art mouse models and biopsies and take a systems biology approach to dissect KC involvement in NAFLD-HCC. Understanding the precise mechanisms underpinning their roles in NAFLD-HCC pathogenesis will allow the design of strategies to manipulate these responses. The final aim of “proteKCt” is therefore to design and test potential therapeutic strategies targeting KCs to prevent or slow NAFLD-HCC development.