Researchers at the University of California, Riverside (UCR) have identified a new strategy for treating systemic lupus erythematosus (SLE), or lupus, an autoimmune disease in which the immune system attacks healthy tissues.
By targeting an imbalance in receptors for the hormone prolactin in disease-causing immune cells, the team reduced inflammatory molecules and harmful immune cells while preserving their normal counterparts.
Prolactin acts as a signalling molecule in many tissues throughout the body. Previous clinical evidence has linked the hormone to lupus, but the mechanisms behind the relationship have remained unclear. The study, published in Experimental and Molecular Medicine and done in human cells and mouse models, points to an important role for a specific form of the prolactin receptor in lupus.
Ameae Walker, a Professor of Biomedical Sciences in the UCR School of Medicine and co-corresponding author of the study, explained that prolactin receptors are produced in two main varieties, long and short. They both bind prolactin via identical regions outside the cell but produce different signalling inside the cell.
“In immune cells from patients with lupus, the balance is shifted toward the long form,” she said. “The long-form prolactin receptor is not a mutant; it’s a perfectly normal form of the receptor. But its expression, and its ratio with the short form, is abnormal in pathogenic immune cells in lupus.”
To address this imbalance, the team developed splice-modulating oligomers (short, synthetic DNA sequences) to alter how cells produce prolactin receptors. These molecules interfere with the processing of receptor messenger RNA and prevent cells from producing the long receptor form while allowing them to continue producing the short forms, which are important in healthy tissues, including the brain and liver.
“This approach could offer an advantage over antagonists and antibodies, which cannot distinguish between the two receptor isoforms because their extracellular regions are identical,” Walker said.
Lupus develops when the immune system produces autoantibodies that attack the body’s own tissues, triggering inflammation and potentially damaging organs. The disease affects people differently, but kidney involvement is common and can have serious consequences. The researchers found their treatment reduced kidney damage in mouse models. Pictured above is a high magnification micrograph of diffuse proliferative lupus nephritis, class IV (PAS [Periodic acid–Schiff] stain).
Before clinical trials can begin, the treatment must be produced and tested under rigorous manufacturing, quality-control and regulatory standards. The study authors are seeking an industry partner to advance the splice-modulating oligonucleotides through preclinical testing and regulatory review.
- Rodrigues Lima-Junior J, Hu Z, Hamane K, et al. Knockdown of the long isoform of the prolactin receptor selectively targets pathogenic immune cells in systemic lupus erythematosus and averts glomerular pathology. Exp Mol Med. Published online November 2, 2026. doi:10.1038/s12276-026-01881-2