# Farnesoid X Receptor Alleviates Cisplatin‐Induced Kidney Inflammatory Injury by Inhibiting Tlr4/NF‐κB Pathway

## TL;DR

This study shows that the Farnesoid X Receptor (FXR) reduces kidney inflammation caused by cisplatin by blocking the Tlr4/NF-κB pathway.

## Contribution

The study reveals a novel mechanism by which FXR alleviates cisplatin-induced kidney injury through suppression of the Tlr4/NF-κB pathway.

## Key findings

- FXR activation with GW4064 reduced inflammation and kidney injury in a mouse model of cisplatin-induced AKI.
- Proximal tubule-specific FXR knockout worsened renal inflammation and increased NF-κB activity.
- In vitro, FXR activation suppressed Tlr4/NF-κB signaling and reduced apoptosis in renal cells.

## Abstract

Inflammatory responses play a critical role in cisplatin‐induced acute kidney injury (AKI). Farnesoid X receptor (FXR) has been shown to mitigate kidney dysfunction, but its mechanism remains unclear. This study aims to explore whether FXR reduces cisplatin‐induced AKI by modulating inflammation. Using a mouse model of AKI, we demonstrated that cisplatin‐induced obvious inflammation in the kidney, evidenced by increased macrophage and neutrophil infiltration, elevated expression of pro‐inflammatory cytokines, including interleukin‐1 beta (IL‐1β), IL‐6, C‐X‐C motif chemokine ligand (CXCL) 1, 2, 5, 20, and C‐C motif chemokine ligand (CCL) 2, and activation of the toll‐like receptor 4 (Tlr4)/nuclear factor‐kappa B (NF‐κB) pathway. RNA sequencing further corroborated these findings, revealing upregulation of inflammation‐related genes and activation of several inflammatory pathways in the kidney after cisplatin administration. Pretreatment with GW4064 (a FXR agonist) reduced inflammatory cytokine expression, immune cell infiltration, and Tlr4/NF‐κB activation, alleviating kidney injury. However, proximal tubule‐specific FXR knockout worsened renal inflammation and increased NF‐κB activity. In vitro, GW4064 decreased pro‐inflammatory cytokine production, suppressed Tlr4/NF‐κB signalling, and reduced apoptosis in cisplatin‐treated renal tubular epithelial cells. Together, these findings demonstrate that FXR significantly alleviates cisplatin‐induced renal inflammation via suppressing Tlr4/NF‐κB signalling. FXR activation may represent a promising therapeutic strategy to mitigate cisplatin‐induced AKI.