Phytomedicine. 2026 Aug 3;160:158681. doi: 10.1016/j.phymed.2026.158681. Online ahead of print.
ABSTRACT
Obesity exacerbates pathological injury in chronic kidney disease and ultimately leads to end-stage renal fibrosis. Extensive studies have demonstrated that scutellarin (SCU), the major active component of the traditional Yunnan medicinal herb Erigeron breviscapus, effectively attenuates tissue fibrosis. However, the molecular mechanisms underlying the protective effects of SCU against obesity-induced renal fibrosis remain unclear. In this study, we first established a high-fat diet (HFD)-induced rat model of renal fibrosis. We assessed renal function, renal morphology, fibrosis-related protein expression, and apoptotic phenotypes. These analyses demonstrated that SCU effectively alleviated renal fibrosis in HFD-fed rats. Consistently, these findings were further validated in a palmitate (PA)-induced HK-2 cell model of renal fibrosis. Subsequently, bulk RNA sequencing identified integrin α9 (ITGA9) as a potential target of SCU. Molecular docking (mean affinity -6.92 ± 0.17 kcal/mol; predicted Ki ≈ 8.46 μM) and surface plasmon resonance (SPR; KD = 5.73 × 10⁻⁶ M) consistently supported a direct interaction between SCU and ITGA9, although the precise binding site was not defined and additional molecular targets of SCU cannot be excluded. ITGA9 was further silenced or overexpressed in HK-2 cells to validate its functional role in renal fibrosis. Subsequent analyses identified the FAK/PI3K/AKT signaling pathway as a key downstream cascade of ITGA9. This pathway was further verified in renal tissues from HFD-fed rats and in HK-2 cells. Our study indicates that SCU alleviates obesity-associated renal injury and tubular epithelial fibrotic responses at least partly through ITGA9, with consequent suppression of FAK/PI3K/AKT signaling in this lipid-overload setting. ITGA9 dependence is most directly supported in PA-treated HK-2 cells, whereas the in vivo data support association and pathway consistency.
PMID:42570613 | DOI:10.1016/j.phymed.2026.158681