Entresto attenuates dexamethasone-induced metabolic dysfunction-associated steatotic features in rats: role of potential SGK1/FOXO3a regulatory pathway and cardio-metabolic axis

Background Prolonged or high dexamethasone (DEXA) exposure can promote steatohepatitis-like liver injury through insulin resistance, oxidative stress, inflammation, mitochondrial dysfunction, and fibrosis. Sacubitril/valsartan (Entresto) exhibits metabolic, anti-inflammatory, and antifibrotic properties that may protect against glucocorticoid-induced hepatic injury. The current study investigates the protective effects of Entresto against DEXA-induced hepatic injury in rats. Methods Male rats were assigned into control, DEXA, and DEXA-treated groups receiving Entresto (30 or 60 mg/kg). Liver function, metabolic parameters, oxidative stress biomarkers, inflammatory and angiogenic mediators, fibrosis-related markers, and key signaling pathways were assessed using biochemical, molecular, histopathological, and immunohistochemical analyses. Results DEXA administration induced hepatic injury, as evidenced by significant elevation of serum ALT, AST, and LDH levels and significant reduction in albumin concentration, accompanied by marked histopathological abnormalities. DEXA also promoted insulin resistance as reflected by increased fasting glucose, insulin, HOMA-IR and impaired OGTT. These changes were accompanied by metabolic dysregulation, including increased PEPCK and GSK expression, reduced glycogen synthase expression, elevated free fatty acids and oxidized LDL, and reduced PPAR-γ and PGC1-α. DEXA further altered IRS-1/AKT/JNK/p-AMPK/FOXO3 signaling, increased oxidative stress and mitochondrial dysfunction, enhanced inflammatory cytokine production and macrophage activation, and upregulated fibrosis-related mediators and renin-angiotensin-aldosterone system (RAAS) activation. In addition, DEXA increased SGK1, TRAF1, and SETD7 expression. Entresto treatment significantly attenuated DEXA-induced hepatic injury improved metabolic homeostasis and insulin sensitivity, enhanced antioxidant defenses, reduced inflammatory and fibrotic responses, and suppressed RAAS overactivation. These effects were associated with modulation of SGK1/FOXO3a signaling and activation of AMPK and PPAR γ-related pathways. Conclusion ENT attenuates DEXA-induced metabolic liver injury with steatotic features by restoring insulin sensitivity, normalizing hepatic triglyceride accumulation, reducing oxidative stress, and modulating inflammatory and pro-fibrotic tissue markers, potentially through regulation of the SGK1/FOXO3a and cGMP/PKG/AMPK pathways crosstalk. These findings suggest that Entresto represents a promising therapeutic approach for mitigating glucocorticoid-induced steatohepatitis-like metabolic liver injury.