Pharmacological role of MLN4924 in cisplatin-induced acute kidney injury

Background: Cisplatin-induced acute kidney injury (Cis-AKI) is a major complication that limits the clinical use of cisplatin, largely due to its cytotoxic effects on renal tubular epithelial cells. Recent studies have shown that MLN4924, a NEDD8-activating Enzyme Inhibitor, can modulate key cellular processes such as Apoptosis, Autophagy, and DNA damage repair. However, its precise role and regulatory mechanisms in the context of Cis-AKI remain largely undefined.

Purpose: This study aimed to elucidate the renoprotective mechanisms of MLN4924 in Cis-AKI.

Materials and methods: A cisplatin-induced nephrotoxicity mouse model and a human renal tubular epithelial (HK-2) damage cellular model were established. Kidney injury was evaluated by histopathology and RNA-sequencing. To explore whether MLN4924 alleviates Cis-AKI via modulation of the p53 and MAPK pathways, we analyzed pathway-specific regulatory changes in response to MLN4924 treatment.

Results: Compared to the group exposed to cisplatin, MLN4924 mitigated the pathological alterations and reduced the expression of molecules associated with renal injury. RNA-sequencing analysis indicated that the p53 and MAPK signaling pathways were inhibited by MLN4924 treatment compared to the cisplatin-exposed group. Moreover, silencing p53 or p38 exacerbates the renal protection conferred by MLN4924 in cisplatin-treated HK-2 cells, while their activation abolishes this effect. Mechanically, p38 activity promoted p53-dependent nephrotoxicity by increasing p53 expression.

Conclusions: MLN4924 exhibits a protective effect against Cis-AKI, as evidenced by inhibition of p53 and MAPK signaling pathways. These results suggest that MLN4924 holds potential as an Adjuvant therapeutic agent in the treatment of kidney diseases associated with chemotherapy.

Cisplatin; MAPK signaling pathway; MLN4924; Renal injury; p53 signaling pathway.