In a mouse study, the diabetes drug tirzepatide dramatically lowered liver fat, inflammation, and scarring, especially in animals that mimicked post‑menopausal hormone loss. It worked by re‑activating energy‑sensing pathways (AMPK) and dialing down growth signals (mTOR), helping the liver burn fat instead of storing it. While the results are promising, they come from rodents, so human effects—especially for women after menopause—still need confirmation.

To investigate the impact of estrogen deficiency on metabolic dysfunction-associated steatotic liver disease progression and evaluate the therapeutic potential of tirzepatide (Tzp), a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, in a murine model of postmenopausal metabolic dysfunction. Female C57BL/6J mice were divided into obese-diabetic (Od) and ovariectomized Od groups, along with lean controls (control, CO). After 12 weeks of dietary intervention, mice received daily Tzp (10 nmol/kg) or vehicle for four weeks. Comprehensive assessments included plasma biochemistry, liver histopathology, AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) complex 1 signaling analysis, and hepatic gene expressions. Od mice developed severe liver pathology, showing 2-3 fold increases in fat accumulation markers, extensive steatosis with hepatocyte ballooning, and 3-4 fold elevated inflammatory markers. Ovariectomy aggravated these effects, increasing fibrosis markers by 2.4-fold and apoptosis signals. Tzp reduced fat deposition by 50%-70%, inflammation by 60%-70%, and fibrosis by 55%. Molecular analyses revealed Tzp restored metabolic balance by: (1) normalizing key energy-sensing pathways (1.5-2 fold AMPK activation; 50% mTOR reduction), (2) reducing fat synthesis signals by 50%-60%, and (3) enhancing fat breakdown pathways (2-2.5 fold increase). Antioxidant defenses were fully restored to normal levels. Principal component analysis demonstrated metabolic improvement, with treated animals showing gene expression patterns closer to healthy controls. Estrogen deficiency synergizes with metabolic dysfunction to aggravate metabolic dysfunction-associated steatotic liver disease progression through AMPK/mTOR pathway dysregulation. Tzp demonstrates comprehensive hepatoprotective effects, ameliorating steatosis, inflammation, and fibrosis while restoring metabolic homeostasis in this model of postmenopausal liver disease.