Pharmacological role of MLN4924 in cisplatin-induced acute kidney injury

• Published in: Biochimica et biophysica acta. General subjects Vol. 1869; no. 10; p. 130842
• Main Authors: Chen, Feng, Yusufu, Ayinigaer, Li, Gang, Gao, Xueyun, Lu, Danqin, Wu, Xiaoyan, Ni, Lihua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2025
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Antineoplastic Agents - adverse effects; Apoptosis - drug effects; Cell Line; Cisplatin; Cisplatin - adverse effects; Cyclopentanes - pharmacology; Cyclopentanes - therapeutic use; Disease Models, Animal; Humans; Male; MAP Kinase Signaling System - drug effects; MAPK signaling pathway; Mice; Mice, Inbred C57BL; MLN4924; p53 signaling pathway; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Renal injury; Tumor Suppressor Protein p53 - metabolism; Renal injury; p53 signaling pathway; MLN4924; MAPK signaling pathway; Cisplatin
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2025.130842

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. This study aimed to elucidate the renoprotective mechanisms of MLN4924 in Cis-AKI. 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. 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. 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. [Display omitted] What is known•Cisplatin's chemotherapy effectiveness is restricted by its kidney toxicity, as it accumulates in renal tubules and causes acute kidney injury through DNA damage, oxidative stress, apoptosis, and so on.•Potential treatments, such as antioxidants and protective compounds, aim to reduce this damage in cisplatin-induced nephrotoxicity. Despite decades of extensive scholarly research and the identification of numerous potential therapeutic targets, an effective and stable program for prevention and treatment has yet to be established.•MLN4924 has been documented to modulate apoptosis, autophagy, cell cycle arrest, DNA repair, and replication, which are key mechanisms involved in cisplatin-induced acute kidney injury (Cis-AKI).•The p53 and MAPK signaling pathways are critical in the pathogenesis of cisplatin-induced nephrotoxicity. Several studies have elucidated potential mechanisms for the cross-talk between the p53 and MAPK signaling pathways in DNA damage and oxidative stress. Innovation•MLN4924 exhibits a protective effect against cisplatin-induced nephrotoxicity.•MLN4924 upregulates both p53 and MAPK signaling pathways, which prevent the renal injury in cisplatin-induced nephrotoxicity.•Ther is a cross-talk between the p53 and MAPK signaling pathways in cisplatin induced nephrotoxicity, and p38 activity enhance p53-dependent cisplatin induced nephrotoxicity by upregulating p53 expression.•The potential of drugs MLN4924 in cisplatin-induced nephrotoxicity may be highly promising.