Curcumol Ameliorates Cisplatin-induced Nephrotoxicity by Targeting TAK1 and Inhibiting MAPK and NF-κB Pathways

Although cisplatin (Cis) is a foundational chemotherapeutic agent, its dose-limiting nephrotoxicity lacks clinically effective drugs. Curcumol (CUR), a bioactive sesquiterpenoid derived from Curcuma zedoariae rhizome, exhibits multi-organ protective effects. However, its therapeutic potential and molecular targets in Cis-provoked acute kidney injury (AKI) remain unexplored.

This study systematically investigated the nephroprotection and underlying mechanism of CUR in Cis-induced nephrotoxicity.

C57BL/6 mice received intraperitoneal administration of 20 mg/kg Cis to induce AKI. Dual-concentration CUR (40/80 mg/kg) was administered pre- and post-treatment in Cis-challenged mice, with longitudinal monitoring of renal function. Human tubular epithelial cells (HK-2 cells) were used to evaluate CUR's nephroprotection in vitro. RNA-sequencing transcriptomics identified pathway-level mechanisms, while structure-based molecular docking (MOD) prioritized target proteins.

CUR exhibited dose-responsive nephroprotection, reducing apoptosis, oxidative stress, and inflammation more effectively than N-acetylcysteine in pre- and post-Cis treatment regimens. Mechanistically, we revealed that nephroprotection of CUR primarily involves suppression of phosphorylation-mediated MAPK/NF-κB pathway activation, thereby mitigating the inflammatory response. Notably, MOD and Cellular thermal shift assay (CETSA) data suggested a direct interaction between CUR and TAK1. Functional validation experiments demonstrated that TAK1 silencing attenuated cisplatin-induced tubular cell injury, and TAK1 activity was essential for CUR's protective effects.

CUR ameliorated Cis-triggered AKI by targeting TAK1 and inhibiting MAPK and NF-κB pathways. These findings suggest that CUR may serve as a promising adjuvant to overcome the primary limitation of Cis.