Pharmacological role of MLN4924 in cisplatin-induced acute kidney injury
- Biochim Biophys Acta Gen Subj. 2025 Sep;1869(10):130842. doi: 10.1016/j.bbagen.2025.130842.
- 1. Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China; Department of Critical Care Medicine, Jingzhou Central Hospital, Jingzhou, Hubei 434000, China.
- 2. Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
- 3. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
- 4. Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China; Department of General Practice, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China. Electronic address: [email protected].
- 5. Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China. Electronic address: [email protected].
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.