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  3. Empagliflozin impact on experimentally induced acetaminophen toxicity: Imprint of mitochondrial dynamics, biogenesis, and cGAS/STING signal in amending liver insult

Empagliflozin impact on experimentally induced acetaminophen toxicity: Imprint of mitochondrial dynamics, biogenesis, and cGAS/STING signal in amending liver insult

  • FASEB J. 2024 Jul 31;38(14):e23816. doi: 10.1096/fj.202400254RRR.
Rehab M El-Gohary 1,  Ahmed Abdeen 2,  Hoda A Ibrahim 1,  Ehab S Taher 3,  Maram M Ghabrial 4,  Reham L Younis 5,  Haidy Khattab 5,  Monira A Seleem 6,  Khairiah M Alwutayed 7,  Ostan Mihaela 8,  Banatean-Dunea Ioan 8,  Mohammad El-Nablaway 9,  Ahmed A Aldarmahi 10 11,  Ateya M Ibrahim 12 13,  Rasha H Al-Serwi 14,  Asmaa A Ghalwash 1
Affiliations

Affiliations

  • 1 Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt.
  • 2 Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt.
  • 3 Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa, Jordan.
  • 4 Department of Anatomy and Embryology, Faculty of Medicine, Tanta University, Tanta, Egypt.
  • 5 Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt.
  • 6 Department of Medical Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt.
  • 7 Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
  • 8 Department of Biology, Faculty of Agriculture, University of Life Sciences "King Michael I" from Timisoara, Timisoara, Romania.
  • 9 Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia.
  • 10 Department of Basic Science, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
  • 11 National Guard- Health Affairs, King Abdullah International Medical Research Centre, Jeddah, Saudi Arabia.
  • 12 Department of Administration and Nursing Education, College of Nursing, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia.
  • 13 Department of Family and Community Health Nursing, Faculty of Nursing, Port-Said University, Port Said, Egypt.
  • 14 Department of Basic Sciences, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
PMID: 39072779 DOI: 10.1096/fj.202400254RRR
Abstract

Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by Real-Time PCR. Histopathological changes and immunohistochemistry of INF-β, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity.

Keywords

PGC‐1α; cGAS/STING pathway; computational modeling; empagliflozin; hepatotoxicity.

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