Ginsenoside Rg5 mitigates adenine-induced renal fibrosis by regulating the SIRT7/NETs/NLRP3 pyroptosis axis

This study examined the protective effects of Rg5 against renal fibrosis and elucidated its underlying immunomodulatory mechanisms. A mouse model of renal fibrosis was generated through adenine administration, and Rg5 was administered orally to assess its preventative effects. Renal tubular epithelial cells (RTECs, HK-2) were stimulated with TGF-β, while bone marrow-derived neutrophils (BMDNs) were activated with PMA to induce neutrophil extracellular trap (NET) formation. Transcriptomic analysis demonstrated that, in mice treated with adenine and adenine+Rg5, the differentially expressed genes (DEGs) were markedly enriched in the NET formation pathway as well as the NOD-like receptor pathway. Moreover, functional analyses further demonstrated that in adenine-induced mice, Rg5 markedly enhanced renal function, decreased extracellular matrix (ECM) accumulation. Mechanistically, Rg5 increased the expression of SIRT7, suppressed NET formation, and inhibited activation of the NLRP3 inflammasome, as indicated by reductions in inflammatory factor levels. Silencing of SIRT7 abolished these protective effects, confirming its pivotal role in mediating Rg5 activity. Furthermore, conditioned medium from BMDNs attenuated fibrotic activation in primary mouse RTECs, emphasizing the significance of neutrophil-epithelial crosstalk. These findings indicate that Rg5 mitigates renal fibrosis by activating SIRT7, thereby suppressing NETs formation and NLRP3 inflammasome activation. This study provides novel insights into the potential application of Rg5 for the early intervention and prevention of renal fibrosis.