Network Pharmacology-Based Exploration of Complementary Molecular Mechanisms of Heat-Clearing (Scutellariae Radix, Coptidis Rhizoma) and Blood-Tonifying Herbs (Angelicae Sinensis Radix, Paeoniae Radix Alba) in Cold Hypersensitivity in Hands and Feet

Cold hypersensitivity in hands and feet (CHHF) affects 20–52% of East Asian populations, is more prevalent in women, and is managed with vasodilators in Western medicine or herbal therapies in traditional East Asian medicine. This study was conducted to compare the pharmacological characteristics of two heat-clearing (HCHs, Scutellariae Radix and Coptidis Rhizoma) and two blood-tonifying herbs (BTHs, Angelicae Sinensis Radix and Paeoniae Radix Alba) used for CHHF. Candidate herbs were selected based on herbology classifications, PubMed searches, and the Korean Medicine Clinical Practice Guideline for CHHF. A total of 61 active compounds and 323 corresponding protein targets with CHHF were retrieved from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), standardized via UniProt, and intersected with CHHF-related genes from GeneCards. Protein–protein interaction networks were con-structed, core targets identified, and functional enrichment analyses performed using Gene Ontology and Reactome databases. A total of 166 herb–CHHF common targets were identified, including 24 shared across all four herbs. HCHs were primarily enriched in hemostasis-, immune-, and signaling-related pathways, whereas BTHs were associated with immune regulation, metabolism, and neuronal modulation. Notably, Scutellariae Radix and Paeoniae Radix Alba showed substantial overlap in enriched pathways. These findings suggest that HCHs and BTHs may act through distinct yet complementary mechanisms in CHHF, providing a mechanistic basis for combined traditional use.