Inhibition of TLR4/TRAF6/NF-κB pathway by empagliflozin mitigates concanavalin A-induced autoimmune hepatitis in mice.
El-Kashef Dalia H, Shawky Noha O, Mahdi Laila, Sewilam Haitham M, Saleh Mohamed A
Abstract
Concanavalin A (ConA) is a commonly used paradigm for inducing autoimmune hepatitis (AIH) in mice. This study was designed to examine the potential prophylactic effect of empagliflozin (Empa) against ConA-induced AIH. Mice received Empa (10 & 25 mg/kg) for 7 days and then injected with ConA (20 mg/kg) on day 7. Empa showed hepatoprotective effects indicated by decreased serum levels of transaminases, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) and elevated levels of albumin. Additionally, Empa corrected the equilibrium between antioxidants and oxidants, and decreased inflammation; this was demonstrated by the down regulation of expression of toll like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κBp65) besides reduction in hepatic levels of myeloid differentiation primary response 88 (MYD88), tumor necrosis factor-α (TNF-α), TNF Receptor Associated Factor 6 (TRAF6), and interleukin (IL-1)β concomitant with increment in levels of IL10 and hepatic expression of nuclear factor erythroid 2-Related Factor 2 (Nrf2). In addition, Empa improved the histopathological alterations induced by ConA and this was clear in micrographs obtained from transmission electron microscopy. Empa could be a useful candidate to attenuate AIH pending clinical evaluation.
Key Findings
- Empagliflozin exhibited hepatoprotective effects by reducing serum transaminases, ALP, and LDH while increasing albumin levels in ConA-induced autoimmune hepatitis in mice.
- Empagliflozin restored antioxidant/oxidant balance and decreased inflammation by downregulating TLR4, NF-κBp65, MYD88, TNF-α, TRAF6, and IL-1β, while increasing IL-10 and Nrf2 expression.
- Histopathological and ultrastructural liver damage induced by ConA was improved following empagliflozin treatment.
Clinical Significance
Empagliflozin shows promise as a potential therapeutic agent to mitigate autoimmune hepatitis by modulating oxidative stress and inflammatory pathways, warranting further clinical evaluation.
Citation
El-Kashef Dalia H, Shawky Noha O, Mahdi Lailaet al.. Inhibition of TLR4/TRAF6/NF-κB pathway by empagliflozin mitigates concanavalin A-induced autoimmune hepatitis in mice. Naunyn-Schmiedeberg's archives of pharmacology. 2026-Apr-11.