Pseudolaric acid B exerts an antifungal effect and targets SIRT1 to ameliorate inflammation by regulating Nrf2/NF-κB pathways in fungal keratitis

Fungal keratitis (FK) is a vision-threatening Infection. We aimed to explore the Antifungal and anti-inflammatory effects of pseudolaric acid B (PAB) on FK and the underlying mechanisms involved. Network pharmacology utilized to acquire the potential target genes, and silent information regulator 1 (SIRT1) was consistently downregulated in Gene Expression Omnibus dataset and clinical samples. Molecular docking analysis showed that PAB and SIRT1 had good binding activity. No toxicity was observed in vivo and in vitro with a PAB concentration below 0.3 μM. PAB exerted its Antifungal activity by destroying the integrity of hyphae, and alleviated the severity of FK in rats by decreasing clinical scores, Fungal burden and inhibiting inflammatory cell infiltration. PAB increased SIRT1 to regulate the crosstalk between nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-B (NF-κB), decreasing the levels of inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6; and Pattern Recognition Receptors, C-type lectin domain containing 7A (Dectin-1), lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), toll like receptor (TLR)-2, and TLR4 both in vivo and in vitro. However, this anti-inflammatory effect of PAB was abolished by the SIRT1 Inhibitor EX527. This study provides new evidence that PAB has Antifungal and anti-inflammatory effects in FK and may provide a novel therapeutic strategy for the treatment of FK.

Fungal keratitis; NF-κB; Nrf2; Pseudolaric acid B; SIRT1.