Integrated Chemical Profiling and Network Pharmacology Establish a Quality Evaluation Framework for the Four Medicinal Parts of Wolfiporia extensa (Peck) Ginns

Wolfiporia extensa (Peck) Ginns (WE) is a fungus widely used in Traditional Chinese Medicine. Its four medicinal parts, Poria (WP), Rubra Poria (RP), Poriae Cutis (PC), and Poria Cum Pini Radix (PPR), are prescribed for distinct therapeutic purposes; however, their quality standards and pharmacological differences remain unclear. This study established reliable quality markers and compared the neuroprotective activities of four medicinal parts of WE. Seven triterpenoids were quantified using validated high-performance liquid chromatography (HPLC) assays, while monosaccharide profiles were analyzed using 1-phenyl-3-methyl-5-pyrazolone-HPLC. The International Commission on Illumination L*a*b* colorimetry and chemometric models were used for authentication. The neuroprotective effects of aqueous extracts were assessed in SH-SY5Y, BV-2, and HOG cell models. Network pharmacology was used to predict compound–target pathway relationships. The content of poricoic acid A (PAA) was the highest in PC; the content of pachymic acid (PA) was the highest in RP; whereas dehydrotumulosic acid (DTUA) was enriched in WP. WP demonstrated the highest mannose and galactose content. The water extract of WP reduced H2O2-induced cytotoxicity in SH-SY5Y cells, whereas the PC extract alleviated L-α-lysophosphatidylcholine-induced injury in human oligodendroglioma cells. Network analysis identified PA, PAA, and poricoic acid B (PAB) as candidate bioactive compounds involved in neuroprotective effects. The PA/PAB ratios of ≥10, 1–9, and ≤1 were used to identify WP, RP, and PC, respectively. L* values of >80, 55–79, and <55 effectively discriminated WP, RP, and PC, respectively. This integrative study identified chemical and functional quality markers and demonstrated distinct neuroprotective profiles in different parts of WE, supporting their standardized and rational application in traditional medicine and nutraceuticals.