Targeting TRAF6/MYD88/TLR4, Nrf2, and VEGF signaling pathways by Tranexamic acid as a Novel Therapeutic Approach Protects Against Isotretinoin-Induced Liver Toxicity in Rats.

Abstract

Background: Isotretinoin is a widely prescribed retinoid for severe acne but is limited by dose-dependent hepatotoxicity. Tranexamic acid (TXA), an antifibrinolytic agent with emerging anti-inflammatory and antioxidant effects, may offer hepatoprotective potential. Aim: This study evaluated whether TXA mitigates isotretinoin-induced liver injury in rats and explored the underlying molecular mechanisms.

Methods: Thirty-two male Wistar rats were assigned to four groups (n = 8 each): control, TXA-only, isotretinoin (ISO, 7.5 mg/kg/day, 30 days), and TXA (100 mg/kg/day for 30 days) + ISO. Serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were measured for hepatic function. Oxidative stress was assessed by hepatic malondialdehyde, myeloperoxidase (MPO), and reduced glutathione (GSH). Inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin1β (IL-1β), interleukin-10 (IL-10), and signaling proteins TNF receptor-associated factor 6 (TRAF6) and nuclear factor erythroid 2-related factor 2 (Nrf2) were quantified by ELISA. Vascular endothelial growth factor (VEGF) and nuclear factor kappa B (NF-κB) expressions by immunohistochemistry. Myeloid differentiation primary response 88 (MYD88) and toll-like receptor-4 (TLR4) protein expression were analyzed via Western blot. Histopathological scoring was performed to evaluate tissue injury.

Results: ISO administration significantly elevated serum ALT and AST by approximately 3-fold (p < 0.001), along with a marked increase in hepatic MDA and MPO, reduced GSH, heightened TNF-α and IL-1β, and suppressed IL-10 (p < 0.05). Hepatic TRAF6, NF-κB, MYD88/TLR4, and VEGF were upregulated significantly (p < 0.05), while Nrf2 was downregulated (p < 0.05), and histology revealed severe degeneration and congestion. TXA co-treatment significantly attenuated these changes (p < 0.05), reducing liver enzyme activities and inflammatory markers while restoring antioxidant defense mechanisms.

Conclusion: TXA pretreatment markedly attenuated these effects, normalizing liver enzymes, restoring oxidative balance, reducing inflammation, and suppressing aberrant signaling. TXA effectively protects against isotretinoin-induced hepatotoxicity, primarily through antioxidant and anti-inflammatory mechanisms.