FSTL1 and NLRP3 Inflammasome Activation in Lupus Nephritis: A Mesenchyme-to-Macrophage Hypothesis

BACKGROUND: Lupus nephritis (LN) is a major cause of morbidity in systemic lupus erythematosus (SLE), and current therapies often fail to prevent end-stage renal disease. Follistatin-like protein 1 (FSTL1), a mesenchymal/stromal-derived glycoprotein, is implicated in renal inflammation. OBJECTIVE: inflammasome axis in LN and to identify gaps relevant to biomarker development and targeted therapy. REVIEW FOCUS: via dual signals: mitochondrial ATP production (activation) and transcriptional upregulation of Nlrp3/pro-caspase-1 (priming), with resulting IL-1β amplifying tubulointerstitial inflammation and fibrosis. We assess evidence that FSTL1 is elevated in SLE sera, whereas direct LN kidney evidence is limited to one Chinese-language immunohistochemical study and NLRP3 colocalization has not been demonstrated in biopsy-proven LN; CKD and UUO models suggest FSTL1 may be present in LN kidney but this remains untested. We also discuss post-translational modifications, extracellular vesicle shuttling, and immunometabolism as unexplored determinants of context-dependent FSTL1 behavior. CONCLUSIONS: The proposed mesenchyme/stroma-to-macrophage axis may offer new opportunities for LN biomarkers and targeted therapy, but current evidence is largely indirect and should be interpreted as a mechanistic framework requiring rigorous translational validation.