Si M, Fu J, Fang M, Lu Y, Huang J, Li H, Wang P, Liao M, Zhu J, Li P, Zhong W, Guo Z, Yang W, Ye Z, Hu H, Yu X. Lysosome-mediated aggregation of galactose-deficient IgA1 with transferrin receptor 1 links to IgA nephropathy. Nat Commun. 2025 Jul 1;16(1):5536. doi: 10.1038/s41467-025-60819-w. PMID: 40593574; PMCID: PMC12219878.

The retention of galactose-deficient IgA1 (Gd-IgA1) in the mesangium is central to IgA nephropathy (IgAN), but its intracellular fate remains unclear. Here, we show that transferrin receptor 1 (TfR1) mediates Gd-IgA1 uptake into mesangial cell lysosomes, where it forms non-digestible aggregates, disrupts lysosomal function, and triggers inflammatory responses. In renal biopsies from IgAN patients, IgA1 aggregates co-localize with TfR1 within lysosomes. In male mice, TfR1 overexpression enhanced lysosomal accumulation of Gd-IgA1, whereas TfR1 knockdown reduced it. Mechanistically, acidic pH strengthens TfR1–Gd-IgA1 binding via the galactose-deficient hinge region and residue R276. While we acknowledge that sialylation commonly found in patient-derived IgA1 might influence TfR1 binding and that other receptors, such as ASGPR, were not evaluated, our findings nonetheless reveal a lysosome-centered mechanism in IgAN and highlight receptor-mediated retention of Gd-IgA1 as a potential therapeutic target.