<scp>TLR2</scp> as a Key Mediator: Bergamottin Protects Against Lead‐Induced Renal Toxicity by Modulating Oxidative Stress and Pyroptosis Pathways

Lead (Pb) toxicity is a major health concern, with the kidney being one of the primary target organs. Current therapeutic strategies for Pb-induced nephrotoxicity are limited, highlighting the need for effective protective agents. Bergamottin (BGM), a natural furanocoumarin, has been reported to possess antioxidant and anti-inflammatory properties, but its role in Pb-induced renal injury has not been elucidated. In this study, we investigated the protective effects of BGM against Pb-induced nephrotoxicity and explored the underlying mechanisms. BGM treatment notably mitigated Pb-induced renal dysfunction, evidenced by significant reductions in serum creatinine and BUN levels. It also effectively ameliorated oxidative stress by reducing MDA and increasing antioxidant enzyme activities. BGM treatment also decreased the expression of NLRP3, caspase-1, and IL-18, thus alleviating pyroptosis-induced renal injury. Moreover, we found that TLR2 is the key factor; silencing TLR2 enhanced BGM's efficacy in protecting against Pb-induced renal damage, while overexpressing TLR2 attenuated BGM's protective benefits in HK-2 cells, highlighting the crucial role of TLR2 in mediating BGM's effects. These findings indicate that BGM could serve as a potential therapeutic agent for Pb-induced nephrotoxicity, with its protective effects primarily mediated through modulation of TLR2 and subsequent reduction in oxidative stress and pyroptosis.