Cell-specific cPGES control of glucocorticoid receptor function drives MASLD progression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder and progresses through distinct pathological stages whose specific drivers remain unclear. Here we show that cytosolic prostaglandin E synthase (cPGES) drives MASLD progression in a cell-type-specific, prostaglandin E2-independent manner by controlling glucocorticoid receptor (GR) function. In hepatocytes, cPGES sequesters GR in the cytosol through HSP90 binding, impairing direct GR-driven transcription of the cholesterol-handling enzymes CYP7B1 and SERPINA1E and promoting cholesterol accumulation and simple steatosis. In macrophages, cPGES suppresses GR nuclear translocation, downregulating metallothioneins (MT1/2), skewing macrophage polarization, and aggravating steatohepatitis. We identified a cPGES inhibitor, SQ-030, that ameliorated steatosis and inflammation in preclinical models. Thus, cPGES is a dual-functioning therapeutic target: its hepatocyte inhibition restores cholesterol homeostasis in early disease, whereas its macrophage blockade resolves inflammation in advanced disease, supporting stage-specific intervention strategies.