UHPLC–HRMS‐Based Tissue Pharmacochemistry and Metabolomics Reveal the Effective Components and Potential Mechanism of Huoxue Huayu Gel Plaster Against Oxaliplatin‐Induced Peripheral Neuropathy

ABSTRACT Huoxue Huayu Gel Plaster (HXHYGP) is a topical traditional Chinese medicine preparation used for oxaliplatin‐induced peripheral neuropathy (OIPN), but its locally exposed bioactive components remain unclear. This study developed an integrated strategy combining pharmacodynamic evaluation, UHPLC‐HRMS‐based tissue pharmacochemistry, untargeted metabolomics, network pharmacology, molecular docking, and qRT‐PCR to identify effective components and explore potential mechanisms. In OIPN rats, HXHYGP improved mechanical and cold sensory dysfunction; reduced plantar tissue injury and inflammatory‐cell infiltration; increased nerve growth factor levels; decreased TNF‐α, IL‐6, and IL‐1β levels; and enhanced nerve conduction velocity. A total of 496 constituents were detected in skin tissue, including 20 tissue‐migrant constituents attributed to HXHYGP. Untargeted metabolomics identified 53 OIPN‐related differential metabolites, of which 42 were significantly reversed after treatment. Correlation analysis and network pharmacology further identified 14 effective components and 98 common targets, with EGFR, PIK3CA, MTOR, RELA, and MAPK14 as key nodes. Molecular docking supported potential component–target interactions, while qRT‐PCR confirmed reduced mRNA expression of these targets after HXHYGP treatment. These findings indicate that HXHYGP may alleviate OIPN by modulating the proposed EGFR/PI3K/AKT/mTOR/NF‐κB signaling network and MAPK14‐associated inflammation. This strategy provides an analytical basis for identifying pharmacodynamic substances and potential quality‐marker candidates in topical traditional Chinese medicine preparations.