LCZ696 (Sac/Val) protects against high-fat diet-induced kidney injury in mice by targeting ROCK2 to suppress ROCK2/NF-κB signaling.

Obesity-related kidney disease (ORKD) is an increasingly prevalent cause of chronic kidney disease (CKD) worldwide, yet effective therapeutic strategies remain limited. LCZ696 (sacubitril/valsartan, Sac/Val), an angiotensin receptor-neprilysin inhibitor, has demonstrated cardio-renal benefits; however, its role and underlying mechanism in ORKD remain unclear. A high-fat diet (HFD)-induced murine model and palmitate (PA)-stimulated NRK-52E cells were used to evaluate the renoprotective effects of LCZ696. Renal function, histopathology, and fibrosis were assessed by biochemical and histological analyses. Transcriptomic sequencing followed by functional enrichment, kinase analysis, molecular docking, and biochemical experiment were performed to identify key regulatory pathways. Mechanistic validation was conducted through ROCK2 overexpression. LCZ696 (Sac/Val) administration significantly improved renal function and alleviated interstitial fibrosis in HFD-fed mice. Transcriptomic analyses identified ROCK2/NF-κB signaling as a potential key pathway. LCZ696 suppressed PA- and HFD-induced activation of ROCK2, as evidenced by reduced MYPT1 phosphorylation, inhibition of IκBα degradation, decreased nuclear accumulation of NF-κB P65, and downregulation of pro-inflammatory cytokines. ROCK2 overexpression largely reversed these effects, supporting its functional involvement. Molecular docking predicted stable binding of Sac and Val within the ROCK2 pocket, which was further supported by CETSA, DARTS, and pull-down assays. LCZ696 (Sac/Val) exerts anti-inflammatory and antifibrotic effects in ORKD, at least in part, through modulation of the ROCK2/NF-κB signaling pathway. These findings identify ROCK2-dependent inflammatory signaling as a potential therapeutic target and suggest that LCZ696 may represent a promising strategy for the treatment of ORKD.