AIM: To reveal the mechanisms of heat-shock transcription factor 4 (HSF4) mutation-induced cataract. METHODS: GSE22362, including 3 HSF4-null lens and 3 wild-type lens, was obtained from Gene Expression Omnibus database. After data preprocessing, the differentially expressed genes (DEGs) were identified using the limma package. Based on Database for Annotation, Visualization and Integrated Discovery (DAVID) tool, functional and pathway enrichment analyses were performed for the DEGs. Followed by protein-protein interaction (PPI) network was constructed using STRING database and Cytoscape software. Furthermore, the validated microRNA (miRNA)-DEG pairs were obtained from miRWalk2.0 database, and then miRNA-DEG regulatory network was visualized by Cytoscape software. RESULTS: A total of 176 DEGs were identified in HSF4-null lens compared with wild-type lens. In the PPI network, FBJ osteosarcoma oncogene (FOS), early growth response 1 (EGR1) and heme oxygenase (decycling) 1 (HMOX1) had higher degrees and could interact with each other. Besides, mmu-miR-15a-5p and mmu-miR-26a-5p were among the top 10 miRNAs in the miRNA-DEG regulatory network. Additionally, mmu-miR-26a-5p could target EGR1 in the regulatory network. CONCLUSION: FOS, EGR1, HMOX1, mmu-miR-26a-5p and mmu-miR-15a-5p might function in the pathogenesis of HSF4 mutation-induced cataract.