Huaier Granule

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.

To evaluate the potential regulatory functions and underlying molecular mechanisms of Huaier in cisplatin resistance of NSCLC.

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 chromatography-mass 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.

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-κB) 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 c-Jun N-terminal protein kinase (JNK).

Huaier suppressed cisplatin resistance of NSCLC cells by inhibiting the JNK/JUN/IL-8 signaling pathway.

Accumulating studies suggest that Huaier exerts anti-tumor effects through intricate mechanisms. Despite extensive research on its efficacy in lung cancer, further investigation is required to elucidate the molecular mechanism of Huaier. The involvement of long noncoding RNAs (lncRNAs) in the anti-lung cancer effects of Huaier remains unknown. In this study, we found Huaier suppressed cell viability, migration and invasion in non-small cell lung cancer (NSCLC) cells. LncRNA sequencing analysis revealed Deleted in lymphocytic leukemia 2 (DLEU2) to be significantly downregulated in Huaier-treated NSCLC cells. Furthermore, DLEU2 silencing was observed to suppress NSCLC progression, while DLEU2 overexpression attenuated the anti-tumor effects of Huaier in NSCLC, thereby promoting cell viability, migration and invasion of NSCLC. The ceRNA role of DLEU2 had been demonstrated in NSCLC, which directly interacted with miR-212-5p to rescue the repression of E74 Like ETS Transcription Factor 3 (ELF3) by this microRNA. Additionally, Huaier was found to regulate the expression of miR-212-5p and ELF3. Functionally, miR-212-5p inhibitor or ELF3 overexpression reversed the effects of DLEU2 silencing or Huaier treatment, resulting in increased colony formation, migration and invasion in NSCLC. Taken together, these results illuminate the mechanism underlying Huaier's anti-tumor effects via the DLEU2/miR-212-5p/ELF3 signaling pathway, which offers novel insights into the anti-tumor effects of Huaier and constitutes a promising therapeutic target for the treatment in NSCLC.