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Updated: May 4, 2026
Early Detection of Drug-Induced Renal Hemodynamic Dysfunction Using Sonographic Technology in Rats
Published on: March 11, 2016
Integrative analysis based on CRISPR screen identifies apilimod as a potential therapeutic agent for
Yunpeng Chu1, Muyun Wei2,3, Zhongyu Cao1
1Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200230, China.
Abstract:
Acute kidney injury (AKI), a life-threatening side effect of cisplatin therapy, significantly limits the drug's therapeutic potential. In this study, we conducted a genome-wide CRISPR/Cas9 knockout screen in human renal tubular epithelial cells, integrating the results with transcriptome analyses and the Connectivity Map (CMap) database. Apilimod and elacridar emerged as the top two candidates of mitigating cisplatin-induced nephrotoxicity, with apilimod demonstrating superior efficacy in drug matrix experiments. Apilimod reduced cisplatin-induced apoptosis, inflammation and reactive oxygen species (ROS) generation. Transcriptome analyses suggested that apilimod may protect against cisplatin-induced nephrotoxicity via modulating lipid metabolism. In vitro experiments revealed that apilimod significantly ameliorated cisplatin-induced lipotoxicity by enhancing lipid clearance and upregulating PGC1α-mediated fatty acid oxidation. Mechanism experiments showed that apilimod induces the nuclear translocation of TFEB through the inhibition of its target, PIKfyve, thereby enhancing PGC1α expression and ameliorating lipotoxicity. These protective effects of apilimod were simulated by siRNA-mediated PIKfyve knockdown and diminished by the PGC1α inhibitor SR-18292 and siRNA targeting TFEB, confirming the role of the PIKfyve/TFEB/PGC1α signaling axis in apilimod's renoprotective effects. In vivo, apilimod alleviated apoptosis, inflammation, and lipid accumulation in a cisplatin-induced AKI mouse model. Additionally, apilimod treatment did not compromise the antitumor effect of cisplatin in cancer cells or tumor-bearing mice. Overall, our study suggests that apilimod could be a promising therapeutic agent for the treatment of cisplatin-induced AKI and revealed its underlying molecular mechanism.
Insights
Apilimod effectively protects against cisplatin-induced acute kidney injury (AKI) by reducing cell death and inflammation. This drug targets lipid metabolism, offering a promising therapeutic strategy for AKI patients undergoing chemotherapy.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Cisplatin chemotherapy can cause acute kidney injury (AKI), limiting its use.
- Identifying effective treatments for cisplatin-induced AKI is crucial.
Purpose of the Study:
- To identify novel therapeutic agents for cisplatin-induced nephrotoxicity.
- To elucidate the molecular mechanisms underlying apilimod's renoprotective effects.
Main Methods:
- Genome-wide CRISPR/Cas9 knockout screen in human renal tubular epithelial cells.
- Transcriptome analysis, Connectivity Map (CMap) integration, and in vitro/in vivo experiments.
- Investigation of the PIKfyve/TFEB/PGC1α signaling pathway.
Main Results:
- Apilimod identified as a potent agent mitigating cisplatin-induced nephrotoxicity.
- Apilimod reduced apoptosis, inflammation, ROS, and lipotoxicity by modulating lipid metabolism via the PIKfyve/TFEB/PGC1α axis.
- Apilimod demonstrated efficacy in a cisplatin-induced AKI mouse model without compromising antitumor activity.
Conclusions:
- Apilimod shows significant promise as a therapeutic agent to prevent cisplatin-induced AKI.
- The PIKfyve/TFEB/PGC1α signaling pathway is a key mediator of apilimod's renoprotective effects.
- Apilimod offers a potential strategy to enhance cisplatin chemotherapy safety.
