Huaier suppresses cisplatin resistance in non-small cell lung cancer by inhibiting the JNK/JUN/IL-8 signaling pathway

Ethnopharmacological relevance: Huaier (Trametes robiniophila Murr), a traditional Chinese medicinal fungus, possesses potent anticancer efficacy and has been used as an adjuvant medication for liver, breast, gastric, intestinal, and non-small cell lung cancer (NSCLC). However, the potential regulatory functions and underlying molecular mechanisms of Huaier in cisplatin resistance of NSCLC remain unknown. Aim: To evaluate the potential regulatory functions and underlying molecular mechanisms of Huaier in cisplatin resistance of NSCLC. Materials and methods: In vitro and in vivo experiments were employed to evaluate the regulatory functions of Huaier in cisplatin-resistant NSCLC cells. Transcriptome sequencing and validation analyses was undertaken to identify the downstream targets of Huaier. Network pharmacology, ultra-performance liquid chromatographymass spectroscopy, and in vitro and in vivo experiments were performed to identify key small molecule drug candidates in Huaier and the regulatory mechanisms these employ to suppress cisplatin resistance in NSCLC. Results: Huaier suppressed cisplatin resistance and cancer cell stemness in cisplatin-resistant NSCLC cells, both in vitro and in vivo. Mechanistically, Huaier could suppress expression of interleuken-8 (IL-8) through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and activator protein-1 (AP-1), two key transcription factors responsible for the activation of IL-8 transcription. Kaempferol was identified as one of the key small molecule compounds in Huaier that could suppress cisplatin resistance by inhibiting the phosphorylation and nuclear translocation of proto-oncogene c-Jun (JUN) by binding and inhibiting the kinase activity of cJun N-terminal protein kinase (JNK). Conclusions: Huaier suppressed cisplatin resistance of NSCLC cells by inhibiting the JNK/JUN/IL-8 signaling pathway.