Targeting IFN signaling as therapeutic option for lupus nephritis.

The course of systemic lupus erythematosus (SLE) is highly heterogeneous, with clinical manifestations varying considerably among patients and multiple immune pathways implicated in disease progression. Regardless of this variability, lupus nephritis (LN) is a frequent organ manifestation of SLE and often progresses to renal failure and dialysis dependence. Despite advances in immunosuppressive therapy, there remains a lack of targeted and individualized treatment options to improve outcomes for patients with LN. Immune dysregulation in SLE is reflected by increased interferon (IFN) activity and signaling, accompanied by the upregulation of canonical IFN‑stimulated genes (ISGs). The resulting IFN signature is widely used as a readout of IFN pathway activation, and numerous studies have evaluated this signature as a biomarker of SLE and LN activity. The specific contributions of type I, II, and III IFNs to this signature remain incompletely defined, although research over the past years has focused primarily on type I IFNs as key drivers. Notably, in the context of LN, renal cells themselves exhibit an IFN signature, underscoring their active contribution to disease progression. To define their suitability as therapeutic targets, the role of IFN activity in LN pathogenesis requires further clarification. Experimental models support distinct LN‑promoting roles of type I, II, and III IFNs, suggesting that targeting upstream triggers of IFN production, in addition to directly inhibiting IFN signaling, may represent promising therapeutic strategies. The recent approval of the type I IFN receptor (IFNαR)-blocking antibody anifrolumab has substantiated the relevance of type I IFN signaling in SLE overall, although its specific benefit in LN remains to be fully established. Based on the studies summarized in this narrative review, increased IFN activity or an IFN signature is detectable in a substantial proportion of patients with SLE and may carry prognostic information but appears insufficient to reliably predict disease flares. In LN in particular, blood-derived IFN activity or signatures alone may not be adequate, and the evaluation of renal tissue or urine-derived cells warrants further investigation. IFN signaling across all three IFN types contributes to LN progression by activating and dysregulating renal resident cells; therefore, targeting pathways that induce IFN expression, alongside direct inhibition of IFN signaling, may offer additional therapeutic opportunities.