The chemokine network in lupus nephritis: pathogenesis, targeted therapies, and future directions

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), affecting more than 50% of SLE patients and remaining a leading cause of end-stage renal disease (ESRD) worldwide. Current standard therapies-glucocorticoids combined with conventional immunosuppressants-fail to achieve sustained remission in 30%-40% of patients and are associated with substantial toxicities, including infections, osteoporosis, and cardiovascular disease. The chemokine system, composed of small secreted proteins and their G protein-coupled receptors (GPCRs), plays a central role in LN pathogenesis by orchestrating pathogenic immune cell infiltration, renal inflammation, and progressive fibrosis. This review synthesizes preclinical and clinical evidence establishing the chemokine network as a rational therapeutic target in LN. We first outline the clinical burden of LN and the limitations of existing therapies, followed by a systematic overview of chemokine biology (classification, structural interactions, and leukocyte trafficking functions). Next, we dissect the pathogenic roles of chemokines in LN, focusing on their secretion by resident renal cells, regulation of immune cell infiltration, and association with renal fibrosis. Subsequently, we evaluate therapeutic advances targeting chemokines, including small-molecule antagonists, monoclonal antibodies, and upstream pathway interventions, while discussing translational challenges (e.g., preclinical-clinical disconnect, complexity of target selection, safety concerns). Finally, we highlight emerging technologies, opportunities for personalized medicine, and long-term research priorities to facilitate the development of chemokine-based therapeutic strategies for LN.