<p>Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerular disease, is a major cause of end-stage renal disease. Ferroptosis, a novel cell death mode induced by iron-dependent phospholipid peroxidation, has been implicated in the progression of chronic kidney disease. Whereas, Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a key enzyme in pro-ferroptotic lipid metabolism that plays a critical role in ferroptosis. In this study, the role of ACSL4-mediated ferroptosis in IgAN progression was investigated by identifying the cell subset ACSL4⁺ Loop of Henle cells (LOHs) in IgAN via single-cell RNA sequencing (scRNA-seq). LOH cell populations were screened by dimensionality reduction with Uniform Manifold Approximation and Projection (UMAP), and ACSL4⁺ LOHs were annotated using cell marker genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) pathway enrichment analyses were performed based on marker genes of ACSL4⁺ LOHs. Cell-cell communication networks were established to infer interactions between ACSL4⁺ LOHs and other cell types. Pathological changes and LOH proportions in IgAN and normal kidney tissues were observed by hematoxylin and eosin (H&amp;E) and Masson staining. Expression levels of ACSL4 in LOHs were determined by immunofluorescence to further investigate its effect on cell function. The proportion of LOHs was significantly elevated in the IgAN group compared to the Control group, and ACSL4 expression was significantly upregulated in LOHs. ACSL4⁺ LOHs were highly expressed in the IgAN group and enriched in the Ferroptosis pathway. Cellular communication between ACSL4⁺ LOHs and ECs, MEs, and PTCs was significantly enhanced in interleukin-6 (IL6) ligand-receptor pairs (IL6R⁺IL6ST). The proportion of LOHs was elevated, and ACSL4 expression was significantly increased in LOHs in the IgAN group. High expression of ACSL4⁺ LOHs, as revealed by scRNA-seq analysis, may enhance ferroptosis in IgAN and trigger inflammatory responses, thereby contributing to disease progression. This study is expected to provide insights into the mechanisms underlying the progression of IgAN.</p>