Mechanistically, the uncovered central driver STAT3 emerges as a critical inflammatory/fibrotic switch integrating the stresses from dual BRUCE and PTEN loss into inflammation/fibrosis in MASLD-to-MASH progression, forcing synergistic overactivation of STAT3, and triggering a feedforward loop of hepatocyte injury, immune cell recruitment, and HSC activation. Here, STAT3 is linked to metabolic dysfunction-associated steatotic liver disease.