Zinc accumulation in macrophages exacerbates metabolic dysfunction-associated steatotic liver disease progression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 1 billion people globally, yet the role of trace elements in its progression remains poorly defined. Here, we identify "macrophage zinc trapping" (i.e., selective zinc accumulation in hepatic macrophages despite systemic zinc depletion) as a critical driver of MASLD. In a cohort of 1069 individuals with MASLD, we found that serum zinc levels were inversely correlated with the disease severity. In a mouse model of MASLD, the hepatic macrophages are marked by zinc accumulation. Macrophage-specific depletion of the zinc exporter Slc30a1 in mice recapitulates human MASLD pathology. In macrophage-specific Slc30a1-deficient mice, trapped zinc activates the Ire1α-Xbp1s pathway, which on the one hand stimulates IL-1β secretion to alter hepatocyte lipid metabolism via IL-1β signaling, and on the other hand enhances direct lipid transfer from macrophages to hepatocytes, thereby synergistically exacerbating steatosis. Notably, treatment with Ire1α inhibitors (4μ8C and STF-083010) or IL-1β blockade (clinically approved anti-IL-1β antibodies) reverse established steatosis, inflammation, and fibrosis in preclinical mouse models. This work redefines the role of zinc in MASLD, shifting the paradigm from systemic deficiency to cell-specific sequestration. It reveals that zinc accumulation in macrophages exacerbates hepatocyte lipid accumulation through both fatty acid transflux and inflammation-driven metabolic reprogramming, uncovering novel therapeutic targets and a clinically actionable biomarker.