Induction of TFEB promotes Kupffer cell survival and reduces lipid accumulation and inflammation in MASLD

Kupffer cells (KCs) are the tissue-resident macrophage of the liver where they serve a critical role in maintaining liver tissue homeostasis and as a filter for circulation. The composition of liver macrophages changes during metabolic dysfunction-associated liver disease (MASLD), with the loss of resident KCs being a hallmark of disease progression. The mechanism(s) and consequences of KC death in metabolic liver disease have yet to be defined. Transcription factor EB (TFEB) is a master regulator of lysosome function and lipid metabolism which has been shown to protect macrophages from lipid stress in atherosclerosis. We hypothesized that TFEB would improve KC fitness in MASLD. To investigate this possibility, we created a transgenic mice in which TFEB was induced specifically in KCs. We found that TFEB induction protected KCs from cell death in two mouse models of MASLD. KC preservation through TFEB induction reduced liver steatosis via a mechanism that was dependent on macrophage lysosomal lipolysis and mitochondrial fatty acid oxidation. The protection from cell death in TFEB KCs was the result of reduced oxidative stress and ferroptosis through a mechanism that involved enhanced NADPH levels. Together, we provide evidence that TFEB promotes KC fitness during MASLD and orchestrates beneficial effects on liver pathology, thus providing potential targets to develop cell-specific therapeutics.