Ganoderic acid C2 alleviates sepsis-associated acute kidney injury via neuraminidase 1-nuclear factor erythroid 2-related factor 2-mediated ferroptosis inhibition

Sepsis-associated acute kidney injury (S-AKI) remains a critical clinical challenge due to its complex pathogenesis, which involves intertwined oxidative stress, ferroptosis, and inflammatory cascades. Despite advances in understanding these mechanisms, existing therapies fail to concurrently target these core pathological drivers, limiting their clinical efficacy. Here, we demonstrate that Ganoderic acid C2 (GA-C2), a triterpenoid from <em>Ganoderma lucidum</em>, inhibits neuraminidase 1 (NEU1) activity to restore nuclear factor erythroid 2-related factor 2 (Nrf2) stability and suppress ferroptosis in S-AKI models. In lipopolysaccharide-stimulated renal tubular epithelial cells and murine sepsis, GA-C2 treatment blocked NEU1-mediated Nrf2 degradation, reducing oxidative stress (via Nrf2/ glutathione peroxidase 4 axis stabilization) and inflammation (via nuclear factor-κB inhibition) while upregulating ferroptosis suppressor protein 1. Molecular docking and cellular thermal shift assays revealed GA-C2 binds directly to NEU1’s catalytic pocket (ARG335/PRO310/VAL311), disrupting its ability to drive Nrf2 ubiquitination and phosphorylation. Crucially, GA-C2 outperformed classical inhibitors by simultaneously targeting both Kelch-like ECH-associated protein 1-dependent and glycogen synthase kinase 3β-driven Nrf2 degradation pathways. These results establish GA-C2 as a NEU1 inhibitor that alleviates S-AKI by coordinately restoring redox balance, suppressing ferroptosis, and attenuating inflammation. By elucidating NEU1’s dual regulatory role in Nrf2 signaling, this work advances the mechanistic understanding of S-AKI and provides a blueprint for multi-target therapeutic design. Furthermore, GA-C2’s efficacy and natural origin highlight the potential of <em>Ganoderma</em>-derived compounds as foundational candidates for nutraceuticals or adjunctive therapies in sepsis management, bridging the gap between mechanistic discovery and translational applications.