Cross-talk between diabetic nephropathy and bone loss: PBMCs-guided discovery of NLRP3-inflammatory signalling.

Diabetic nephropathy (DN), a major driver of end-stage kidney disease, elevates the risk for osteoporosis (OP) and its clinical precursor, low bone mineral density (low BMD), indicating broader systemic effects. While peripheral blood mononuclear cells (PBMCs) participate in both conditions, their common mechanisms remain poorly understood. This study aimed to identify common biomarkers and pathways linking DN to OP/low BMD by analyzing transcriptomic datasets from patients with these conditions. Using weighted gene co-expression network analysis (WGCNA), machine learning, and differential expression validation, we identified NLRP3 as a central hub gene. Functional analyses connected NLRP3 to pro-inflammatory pathways and immune cell activation. Single-cell data showed specific NLRP3 overexpression in DN patient macrophages, which exhibited heightened osteoclast differentiation capability. Protein analysis confirmed elevated NLRP3 levels in DN cases. In conclusion, PBMCs from DN patients with comorbid osteoporosis show upregulated NLRP3 expression and inflammasome activation, which may drive systemic inflammation and bone loss. These results clarify the pathological link between DN and OP/low BMD and highlight NLRP3 as a potential diagnostic marker and therapeutic target.