Toxicology and applied pharmacology · 2025
Apremilast attenuates methotrexate-induced hepatic injury in rats; insights into TLR4/NF-κB/P38 MAPK/caspase-3 and α-klotho/Nrf2/HO-1 signaling network interplay.
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Mohyeldin Reham H, Sharata Ehab E, Abdelnaser Mahmoud, Ibrahim Ayman M, Attya Mina Ezzat, Kotb Al Shaimaa Mahmoud, S Aboalela Ahmed, Rofaeil Remon Roshdy
Аннотация
AIM: This study aimed to assess the preventive potential of apremilast (APRE) against methotrexate (MTX)-induced hepatotoxicity through modulation of Nrf2/HO-1 and TLR4/NF-κB/p38 MAPK/Caspase-3 pathways.
MAIN METHODS: Male rats were assigned to the control, apremilast, methotrexate, and methotrexate + apremilast groups. Histopathological investigation and analysis of the serum hepatotoxicity indicators (AST, ALT, ALP, and GGT) were used to evaluate the hepatic toxicity. Testing for hepatic MDA and GSH was conducted. The levels of hepatic TNF-α, IL-6, Nrf2, α-klotho, HO-1, and cleaved caspase-3 were measured using the ELISA method. Using an immunohistochemistry method, the expression of NF-κB p65 was investigated. Western blotting was used to examine the expression of TLR4 and p38 MAPK, and docking experiments were performed on all proteins that were investigated.
KEY FINDINGS: The liver was significantly affected, as evidenced by higher levels of ALT, AST, ALP, and GGT as well as increased levels of hepatic MDA, TNF-α, IL-6, BAX, Caspase-3, and decreased GSH activity and BCL-2 expression. These outcomes were linked to inhibition of α-klotho/Nrf2/HO-1 signaling and activation of TLR4/NF-κB/p38 MAPK/Caspase-3. Co-treatment with APRE markedly improved all biochemical and pathological alterations evoked by MTX.
CONCLUSION: Apremilast mitigates the harmful effects of methotrexate on the liver by activating signaling cascades that include Nrf2/HO-1, while downregulating TLR4/NF-κB/p38 MAPK/Caspase-3.
MAIN METHODS: Male rats were assigned to the control, apremilast, methotrexate, and methotrexate + apremilast groups. Histopathological investigation and analysis of the serum hepatotoxicity indicators (AST, ALT, ALP, and GGT) were used to evaluate the hepatic toxicity. Testing for hepatic MDA and GSH was conducted. The levels of hepatic TNF-α, IL-6, Nrf2, α-klotho, HO-1, and cleaved caspase-3 were measured using the ELISA method. Using an immunohistochemistry method, the expression of NF-κB p65 was investigated. Western blotting was used to examine the expression of TLR4 and p38 MAPK, and docking experiments were performed on all proteins that were investigated.
KEY FINDINGS: The liver was significantly affected, as evidenced by higher levels of ALT, AST, ALP, and GGT as well as increased levels of hepatic MDA, TNF-α, IL-6, BAX, Caspase-3, and decreased GSH activity and BCL-2 expression. These outcomes were linked to inhibition of α-klotho/Nrf2/HO-1 signaling and activation of TLR4/NF-κB/p38 MAPK/Caspase-3. Co-treatment with APRE markedly improved all biochemical and pathological alterations evoked by MTX.
CONCLUSION: Apremilast mitigates the harmful effects of methotrexate on the liver by activating signaling cascades that include Nrf2/HO-1, while downregulating TLR4/NF-κB/p38 MAPK/Caspase-3.