Xanthatin synergizes with cisplatin to suppress homologous recombination through JAK2/STAT4/BARD1 axis in human NSCLC cells

Xanthatin (Xa) is a bicyclic sesquiterpene lactone identified from the plant Xanthium L. with impressive antitumor activity, but the role of Xa in non‐small cell lung cancer (NSCLC) is not known. Here we found that Xa inhibits proliferation, migration, invasion and induces apoptosis in NSCLC cells. RNA sequencing and Gene set enrichment analysis revealed that Xa significantly activates p53 pathway and suppresses E2F targets, G2M checkpoint and MYC targets in A549 cells. Among these changed genes, the down‐regulated gene BARD1 triggered by Xa was identified as a candidate involved in Xa’s antitumor effect because of its vital role in homologous recombination (HR). Further studies demonstrated that Xa inhibits HR through the BARD1/BRCA1/RAD51 axis, which enhances cell sensitivity to cisplatin. Mechanistic studies showed that Xa inhibits BARD1 through the JAK2/STAT4 pathway. Our study revealed that Xa is a promising drug to treat NSCLC, especially in combination with conventional chemotherapy.