ZNF131-BACH1 transcriptionally accelerates RAD51-dependent homologous recombination repair and therapy-resistance of non-small-lung cancer cells by preventing their degradation from CUL3

<b>Rationale:</b> Both bulk RNA-sequencing and GEO database upon chemotherapy to non-small cell lung cancer (NSCLC) cells reveal that ZNF131 (Zinc Finger Protein 131) maybe a crucial transcriptional factor involved. However, it is a recently discovered protein with largely unexplored expression patterns and biological functions. <b>Methods:</b> Bioinformatics analyses and immunohistochemistry staining were assessed to detect both mRNA and protein levels of ZNF131 in NSCLC specimens and cell lines. Next, colony formation assay, MTT assay, EdU assay, transwell assay, flow cytometric analysis, sphere formation assay, western blotting analysis, mouse xenograft model analysis, immunofluorescence assay, and reverse transcriptase-polymerase chain reaction were performed to investigate the effect of ZNF131 interaction on proliferation, invasion, stemness, chemotherapy sensitivity. RNA-sequencing assay, RNA-microarray, and ChIP-sequencing assay were used to identify candidate downstream target genes. Further, liquid chromatography-tandem mass spectrometry analysis, GST pull-down assay, and immunoprecipitation assays were performed to evaluate the interactions between ZNF131, BACH1, and CUL3. <b>Results:</b> ZNF131 was elevated in NSCLC specimens and cell lines, which significantly correlates with advanced TNM stage and poor prognosis in NSCLC patients. ZNF131 overexpression promotes NSCLC cell proliferation, invasion, and stemness both <i>in vitro</i> and <i>in vivo</i>. ZNF131 appears to target the RAD51 gene within a well-defined region (-668bp to -403bp) of the RAD51 promoter. ZNF131 contributes to RAD51-dependent homologous recombination (HR), primarily through its Zinc Finger and BTB domains. ZNF131-BACH1 interaction, mediated by their respective BTB domains, enhances the stability of both proteins, effectively preventing their ubiquitin-mediated degradation by CUL3. The ZNF131-BACH1 partnership significantly amplifies RAD51-dependent HR, resulting in expedited resistance to both radiotherapy and chemotherapy in NSCLC patients. Desoxyrhaponticin was shown to halt NSCLC progression and orchestrate a synergistic effect together with chemotherapy at least partially by targeting ZNF131. <b>Conclusions:</b> Our findings indicate that ZNF131 exhibits heightened expression in NSCLC, driving essential processes such as proliferation, invasion, and stemness by transcriptionally activating RAD51. The ZNF131-BACH1 interaction serves as a crucial enhancer, further boosting RAD51 transcription and ultimately accelerating therapy resistance in NSCLC.