Integrative computational approach to elucidate the efficacy of cordyceps in managing lupus nephritis: from molecular targets to clinical applications.

BACKGROUND: Despite advances in immunosuppressive therapies, lupus nephritis (LN) continues to be a major contributor to morbidity and mortality. The scarcity of reliable biomarkers for predicting renal outcomes further complicates clinical management. While Cordyceps is recognized for its immunomodulatory properties as a medicinal fungus, its therapeutic potential in LN remains underexplored. Moreover, it is unclear whether its molecular targets identified through screening constitute viable therapeutic interventions for this disease. METHODS: Network pharmacology was integrated with LN-associated databases and transcriptomic analysis of GSE200306. Protein-protein interaction, Gene Ontology, and pathway-enrichment analyses were performed to identify candidate targets and biological processes. Molecular docking was used to evaluate predicted interactions between Cordyceps constituents and selected proteins. MAPK1 and CFB expression was further assessed using Nephroseq, an independent transcriptomic cohort (GSE112943), and immunohistochemistry in renal tissues from 30 patients with LN and 10 controls. A multivariable model incorporating age, sex, estimated glomerular filtration rate, MAPK1, and CFB was evaluated using receiver-operating-characteristic, calibration, and decision-curve analyses. RESULTS: Seven active constituents and 111 putative Cordyceps targets were identified. Intersection with 707 LN-associated genes yielded 26 candidate therapeutic targets enriched in apoptosis, inflammatory responses, complement activation, and NF-κB and PI3K-Akt signaling. Analysis of GSE200306 identified 89 differentially expressed genes, among which MAPK1 and CFB intersected with the Cordyceps-LN target network. Both genes were upregulated in LN kidneys, enriched in the tubulointerstitial compartment, inversely associated with renal function, and supported by immunohistochemistry. The combined model achieved an area under the curve of 0.954 and showed potential clinical utility. In GSE112943, MAPK1 was significantly upregulated, whereas CFB showed a concordant but nonsignificant increase. Docking suggested plausible interactions between peroxyergosterol and MAPK1/CFB but did not establish direct target engagement. CONCLUSIONS: Collectively, these findings identify MAPK1 as a reproducible candidate biomarker and CFB as a compartment-sensitive candidate biomarker in LN. Both molecules represent hypothesis-generating intervention nodes through which Cordyceps-derived constituents may act; direct target-engagement and functional studies are required before they can be considered actionable therapeutic targets.