Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome and often leads to end-stage renal disease. However, the underlying pathophysiological mechanisms that contribute to disease progression require further investigation to establish appropriate therapeutic targets and biomarkers. This study aimed to clarify the molecular mechanisms underlying FSGS by focusing on differentially expressed genes (DEGs) and lipid metabolism-related genes (LMRGs). We utilized the GSE69814, GSE129973, and GSE121233 datasets, which comprise glomerular transcriptomes from patients with FSGS, minimal change disease (MCD), and unaffected kidney tissues. We identified 2,459 DEGs from the GSE69814 dataset and 982 DEGs from the GSE129973 dataset. These DEGs intersected 1,450 LMRGs, resulting in 56 differentially expressed LMRGs (DELMRGs). Enrichment analysis revealed that these DELMRGs were primarily involved in fatty acid metabolic processes
localized in microbodies, peroxisomes, and mitochondrial matrices
and exhibited oxidoreductase activity. Protein-protein interaction networks were constructed using Cytoscape, and five hub DELMRGs (enoyl-CoA hydratase, short chain 1 [ECHS1], EHHADH, IDH1, SUCLG1, and ALDH3A2) were identified using multiple algorithms. We assessed the diagnostic performance using receiver operating characteristic curves and expression levels from the GSE121233 dataset, and found that ECHS1 and ALDH3A2 showed strong diagnostic potential. Immunohistochemical verification of clinical specimens from children confirmed significant expression of ECHS1 in FSGS compared with that in normal and MCD tissues. This study highlights ECHS1 as a potential biomarker for pediatric FSGS, suggesting a potential role in early diagnosis or personalized treatment, offering insights into its pathogenesis and paving the way for targeted therapeutic strategies.