Entresto attenuates dexamethasone-induced metabolic dysfunction-associated steatotic features in rats: role of potential SGK1/FOXO3a regulatory pathway and cardio-metabolic axis
- 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University
- 2Faculty of Health Science Technology, Mansoura National University
Abstract
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.
Related
- Gudan Wan attenuates metabolic dysfunction-associated steatohepatitis by modulating autophagy and the Bcl-2/Caspase-3/Caspase-8 apoptotic axis
- Macrophage interferon regulatory factor 7 aggravates the progression of metabolic dysfunction-associated steatohepatitis.
- D-allulose attenuates dyslipidemia, oxidative stress, and inflammation in high-fat-diet-induced metabolic dysfunction-associated steatotic liver disease in rats.
- Quercetin Attenuates Metabolic Dysfunction and Reshapes Hypothalamic m6A-Related, Leptin–Insulin, and Melanocortin-Associated Transcription in High-Fat-Diet-Fed Rats
- Gamma-Oryzanol Solid Dispersion Attenuates Dexamethasone-Induced Depressive-like Behaviors in Rats Associated with Calbindin-1 and Calcium Signaling.
BibTeX
@article{alreshidi2026entresto,
title = {{Entresto attenuates dexamethasone-induced metabolic dysfunction-associated steatotic features in rats: role of potential SGK1/FOXO3a regulatory pathway and cardio-metabolic axis}},
author = {Mutni Kh. Alreshidi and Karim M. Saad and Marwa S. Zaghloul and Manar A. Nader},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1961803},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1961803/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Entresto attenuates dexamethasone-induced metabolic dysfunction-associated steatotic features in rats: role of potential SGK1/FOXO3a regulatory pathway and cardio-metabolic axis
AU - Mutni Kh. Alreshidi
AU - Karim M. Saad
AU - Marwa S. Zaghloul
AU - Manar A. Nader
PY - 2026
DA - 2026/10/14
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1961803
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1961803/full
AB - 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.
SN - 1663-9812
ER -