Metabolic dysfunction-associated steatohepatitis (MASH) is associated with the activation of Kupffer cells (KCs) and hepatic stellate cells, at which point a metabolically stressed hepatocyte becomes integral to the progression of the disease. We observed a significant reduction in the level of alpha-1-antitrypsin (A1AT), a hepatocyte-derived secreted factor, in both patients with MASH and mice fed a fast-food diet (FFD). KC-mediated hepatic inflammation, most notably IL-1β, led to the transcriptional inhibition of A1AT by HNF4α. In quintuple Serpina1a-e knockout mice, ablation of A1AT worsened MASH through increased activity of proteinase 3 (PR3), a proinflammatory protease produced by F4/80