Shenxiaohuangqi decoction alleviates oxaliplatin-induced peripheral neuropathy by inhibiting cuproptosis

This study aimed to investigate the therapeutic effect and mechanisms of Shenxiaohuangqi decoction (SXHQD) against oxaliplatin-induced peripheral neuropathy (OIPN). Ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was employed to analyze the composition of SXHQD, identifying 26 major compounds. Pain responses were assessed using behavioral tests. Morphological changes in the dorsal root ganglion (DRG) and sciatic nerve were observed via transmission electron microscopy (TEM). Intraepidermal nerve fiber density (IENFD) was evaluated by immunofluorescence staining. Copper ion concentrations in tissues and cells were measured using assay kits. The expression of cuproptosis-related proteins and genes was detected through immunohistochemistry, Western blot, and real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). Cell viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In vivo , SXHQD reversed mechanical allodynia, thermal and cold hyperalgesia, protects against oxaliplatin-induced IENF loss, and rescued oxaliplatin-induced mitochondrial dysfunction in DRG and sciatic nerve. In vitro , SXHQD stimulated the neurite outgrowth. SXHQD inhibited cuproptosis both in vitro and in vivo . SXHQD alleviates OIPN by upregulating Copper Metabolism MURR1 domain protein 1 ( COMMD1 ) and ATPase Copper Transporting Alpha ( ATP7A ) to restore copper homeostasis and inhibit cuproptosis, without compromising the antitumor activity of oxaliplatin, positioning it as a promising therapeutic candidate.