Mono(2-ethylhexyl) phthalate activates JNK signaling via TLR4-MD2 binding to induce podocyte injury in chronic kidney disease

Dec 2, 2025Journal of hazardous materials

Chemical Mono(2-ethylhexyl) Phthalate may cause kidney cell damage by activating stress signals through immune receptors in chronic kidney disease

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Abstract

Mono-2-ethylhexyl phthalate (MEHP) was associated with a reduction in estimated glomerular filtration rate (eGFR) and an increase in albuminuria in patients with chronic kidney disease.

MEHP exposure preferentially induced glomerular injury while renal tubules remained unaffected.
Toll-like receptor 4 (TLR4) may mediate MEHP-induced damage to podocytes through activation of the MyD88-JNK pathway.
In vitro, MEHP activated TLR4, leading to downstream MyD88 recruitment and JNK phosphorylation, which resulted in podocyte injury.
MEHP directly interacted with TLR4 and MD2, promoting the formation of the TLR4-MD2 complex and JNK activation.
Inhibition or genetic deletion of TLR4 reduced MEHP-related nephrotoxic effects in models of acute kidney injury and chronic kidney disease.

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Phthalates (PAEs), widely used in plastics and consumer products, have raised growing concern due to the potential adverse health effects of their metabolites. While several epidemiological studies have linked PAE metabolites to nephrotoxicity, most have focused on exposure-response associations, leaving their molecular targets and mechanisms insufficiently defined. Here, we observed that mono-2-ethylhexyl phthalate (MEHP) was associated with reduced estimated glomerular filtration rate (eGFR) (WQS weight = 0.31) and increased albuminuria (WQS weight = 0.15) in patients with chronic kidney disease (CKD). In vivo, MEHP exposure preferentially induced glomerular injury, characterized by foot process effacement, while renal tubules remained unaffected. A genome-wide CRISPR-Cas9 screen highlighted toll-like receptor 4 (TLR4) as a potential mediator of MEHP-induced podocyte damage via MyD88-JNK pathway activation. In vitro experiments demonstrated that TLR4 activation by MEHP triggered downstream MyD88 recruitment and JNK phosphorylation, leading to podocyte injury. Notably, MEHP did not change TLR4 expression levels but directly interacted with TLR4 at Glu439 and MD2 at Arg90, promoting dimerization of the TLR4-MD2 complex and subsequent JNK activation. Furthermore, inhibition or genetic deletion of TLR4 mitigated MEHP-related nephrotoxic responses in acute kidney injury and CKD models. These findings suggest a TLR4-dependent mechanism that may contribute to MEHP-associated kidney effects, supporting the importance of continued efforts to reduce PAE exposure.

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Mono(2-ethylhexyl) phthalate activates JNK signaling via TLR4-MD2 binding to induce podocyte injury in chronic kidney disease

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