Objective To evaluate the efficacy and safety of external application of Jinhuang Ointment in treating hand-foot skin reaction (HFSR) associated with multiple kinase inhibitors (MKIs) and to preliminarily explore its mechanism of action using network pharmacology.

Methods A total of 80 patients were randomly assigned to experimental group and control group, with 40 patients in each group. The control group received oral vitamin B₆ tablets combined with topical urea cream applied to the affected areas, while the experimental group received topical Jinhuang Ointment applied to the affected limbs with HFSR. The National Cancer Institute (NCI) adverse reaction grading, Numerical Rating Scale (NRS) scores, Karnofsky Performance Status(KPS) scores, and incidence of skin allergic reactions were compared between the two groups before treatment and at days 3, 7, 14, and 28 after treatment. Network pharmacology analysis was conducted by screening active ingredients and related disease targets from the formula using the TCMSP database. Core targets were identified using Cytoscape software and its CytoHubba plugin, followed by gene ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of core targets via the Metascape platform. A "drug-ingredient-target-pathway-disease" network was constructed for visualization.

Results Two patients in the control group and one in the experimental group were lost in follow-up, resulting in 39 patients in the experimental group and 38 in the control group for final analysis. At day 28, the proportion of patients with grade 0 HFSR in the experimental group was significantly higher than that in the control group (P < 0.01). Additionally, the proportion of patients with grade 2 HFSR in the experimental group waslower than that in the control group, and no patients in the experimental group had grade 3 HFSR, with statistically significant differences (P < 0.01). At day 28, the experimental group showed significant improvements in KPS and NRS scores compared with the control group (P < 0.01). A total of 122 drug-disease common targets were identified using the TCMSP platform, and 30 core targets were screened. GO and KEGG enrichment analyses revealed that the core targets were primarily involved in the JAK/STAT and PI3K/AKT signaling pathways and affected vascular endothelial growth factor-related factors.

Conclusion External application of Jinhuang Ointment demonstrates significant efficacy in treating MKIs-associated HFSR, effectively alleviating pain and improving quality of life with good safety. Jinhuang Ointment contains 136 active ingredients and 30 potential core targets, and its therapeutic effects may be mediated through modulation of the JAK/STAT, PI3K/AKT, and other signaling pathways.