Lupiwighteone Ameliorates Diabetic Nephropathy-Induced Renal Fibrosis via SIRT1/NF-κB Signaling Pathway-Mediated Inflammatory Response

Diabetic nephropathy (DN) is a severe diabetic complication leading to end-stage renal disease (ESRD), driven by inflammation and fibrosis. Lupiwighteone (Lup), an isoflavone with documented anti-inflammatory and anticancer activities, remains uncharacterized regarding its therapeutic potential for DN. This study investigated the protective effects of lupiwighteone against DN-induced renal fibrosis and its underlying mechanisms in db/db mice and high glucose-induced HK-2 cells. Lupiwighteone treatment significantly improved metabolic parameters and renal function in db/db mice, accompanied by attenuated renal fibrosis. Network pharmacology analysis identified Sirtuin 1 (SIRT1) as a potential target. Mechanistically, lupiwighteone upregulated renal SIRT1 expression, inhibited nuclear factor-κB (NF-κB) activation, and reduced pro-inflammatory cytokines in db/db mice. In vitro, lupiwighteone activated SIRT1 in high glucose-treated HK-2 cells, suppressed NF-κB signaling, and decreased fibrosis markers. Collectively, lupiwighteone ameliorates DN-induced renal fibrosis via the SIRT1/NF-κB pathway, highlighting its potential as a dietary supplement for preventing renal fibrosis in DN.