SOCS1 orchestrates ferroptotic renal injury via GPX4 ubiquitination in hyperuricemia.

Hyperuricemia (HUA)-induced renal injury involves elusive molecular mechanisms. This study uncovers suppressor of cytokine signaling 1 (SOCS1) as a pivotal mediator of hyperuricemic nephropathy through ferroptosis regulation. In a murine HUA model, we observed significantly elevated serum uric acid, impaired renal function, heightened inflammation, and activated ferroptosis. In vitro studies using uric acid-treated renal tubular cells demonstrated that SOCS1 deficiency alleviated ferroptotic cell death, reduced inflammatory responses, and preserved mitochondrial integrity. Mechanistically, SOCS1 directly interacts with glutathione peroxidase 4 (GPX4) to promote its ubiquitin-dependent proteasomal degradation, as validated by co-immunoprecipitation and protein stability assays. Crucially, pharmacological induction of ferroptosis abolished the protective effects of SOCS1 knockdown, while GPX4 inhibition counteracted its anti-ferroptotic function. In vivo delivery of renal-targeted SOCS1 shRNA via AAV9 vectors attenuated hyperuricemic nephropathy, ameliorating histological damage and suppressing both ferroptosis and inflammation. Our findings establish a pathogenic axis wherein SOCS1 drives hyperuricemic renal injury by facilitating GPX4 ubiquitination and subsequent ferroptosis activation, highlighting this pathway as a promising therapeutic target.