Ginsenoside Compound K Mitigates Mitochondrial Fission Through Bile Acid Receptors/YAP Signaling to Counteract Podocyte Injury in Lupus Nephritis

Irreversible renal damage in lupus nephritis (LN) results from critical podocyte injury. Disruption in the actin Cytoskeleton initiates mitochondrial fission to exacerbate podocyte injury. While ginsenoside compound K (CK) alleviates podocyte injury in lupus-prone mice, its mechanism in regulating mitochondrial dynamics underlying remains elusive. Based on the open-source single-cell RNA Sequencing dataset, this study clarified CK's role in alleviating podocyte injury in MRL/lpr mice by regulating cytoskeleton-mediated mitochondrial fission and elucidated the molecular mechanisms underlying the BA receptor-YAP axis. MRL/lpr mice were administered CK (20 or 40 mg/kg) for 10 weeks. Renal function and pathological changes were evaluated, along with renal metabolite profiles and metabolomics analysis. We analyzed publicly available single-cell RNA Sequencing data to specifically profile gene mapping and enrichment analysis during immune-mediated renal injury. Furthermore, podocyte-based in vitro assays were conducted to investigate the impact of the BA receptors-YAP axis on mitochondrial dynamics. CK effectively cleared anti-dsDNA antibodies, attenuated systemic inflammation, and improved renal function through resolving immune complex deposition. Mechanistically, CK restored actin Cytoskeleton integrity via Rho GTPase regulation and reshaped BA metabolism to activate TGR5/FXR receptors in podocytes. This dual action suppressed DRP1 s616 phosphorylation, inhibiting excessive mitochondrial fission, regulating while enhancing TFAM-mediated mtDNA replication for mitochondrial homeostasis. Concurrently, CK attenuated podocyte Apoptosis through Hippo signaling inhibition and YAP activation. In conclusion, CK ameliorates podocyte injury by preventing excessive mitochondrial fission through the BA receptors-YAP axis, thus providing a potential therapy for LN.

bile acid receptor; ginsenoside compound K; lupus nephritis; mitochondrial dynamics; podocyte.