Diltiazem Mitigates Acute Liver Injury by Targeting NFκB-TXNIP/NLRP3 Axis in Rats: New Insights Beyond Calcium Channel Blockade

Acute liver injury is characterized by the rapid onset of inflammation in the liver, which in turn plays a role in the development of hypertension. Additionally, hypertension increases susceptibility to liver diseases associated with inflammatory states. Recently, the antihypertensive drug diltiazem has demonstrated anti-inflammatory properties and has been shown to inhibit the expression of the thioredoxin-interacting protein (TXNIP), an upstream regulator of the NOD-like receptor pyrin-3 (NLRP3) inflammasome pathway. In our quest for an optimal therapeutic intervention for liver inflammatory diseases, we investigated the effects of diltiazem. Herein, we employed a multi-step approach integrating computational target prediction, network analysis, and molecular docking with experimental validation to explore potential interactions between diltiazem and TXNIP. Our investigations in rats with thioacetamide-induced liver injury revealed the anti-inflammatory potential of diltiazem, likely due to the suppression of the NLRP3 signaling pathway via targeting TXNIP. Furthermore, diltiazem suppressed the priming signal induced by nuclear factor kappa-B (NFκB) activation, as well as subsequent inflammasome components, including cleaved caspase-1, gasdermin D, IL-1β, and IL-18. Consequently, diltiazem exhibited anti-pyroptotic effects in the injured liver. Additionally, diltiazem was observed to reduce BCL-2-associated X-protein (Bax) levels, increase B-Cell Lymphoma-2 (BCL2) levels, and decrease the tissue expression of cleaved caspase-3, indicating potential anti-apoptotic effects. These effects were reflected in improved liver weight-to-body weight ratio, liver histology, oxidative stress parameters, and liver function. In conclusion, diltiazem shows promise as a protective agent for liver inflammatory diseases. Further research is warranted to translate these preclinical results into effective strategies for improving liver health.