SH3YL1-TLR5 complex-mediated vicious cycle contributes to FSGS pathogenesis

The mechanisms underlying focal segmental glomerulosclerosis (FSGS), particularly podocyte damage, remain unclear. We found that patients with FSGS have significantly elevated serum and urine levels of SH3YL1, especially in more severe cases. Adriamycin stimulates SH3YL1 secretion, which induces proinflammatory cytokines and enhances podocyte injury. The receptor for secreted SH3YL1 is identified as Toll-like receptor 5 (TLR5), with the ectodomain specifically binding SH3YL1 at an affinity of 1.49 × 10^-8 M. In murine FSGS model, knockout of TLR5 or SH3YL1 alleviated renal inflammation, podocyte damage, sclerosis, and tubular injury. The proposed mechanism involves a vicious cycle where renal injury induces SH3YL1 secretion, promoting podocyte death and local inflammation, which further amplifies SH3YL1 secretion. We developed a therapeutic antibody that neutralizes secreted SH3YL1, effectively reducing podocyte death and sclerosis. These findings suggest that the SH3YL1-TLR5 axis drives podocyte damage in FSGS and that the antibody could serve as a promising therapeutic intervention.