KDM6B Inhibition Enhances Chemotherapeutic Response in Small Cell Lung Cancer via Epigenetic Regulation of Apoptosis and Ferroptosis

Background: Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression and the frequent emergence of resistance to standard chemotherapeutic agents such as cisplatin (DDP) and etoposide (VP16), resulting in poor clinical outcomes. Methods and Results: To elucidate mechanisms underlying chemoresistance, we conducted a genome-wide CRISPR/Cas9 knockout screen, which identified the histone demethylase KDM6B as a critical mediator of drug resistance in SCLC. Pharmacological inhibition of KDM6B using GSKJ1 markedly enhanced the sensitivity of drug-resistant SCLC cells to DDP and VP16. GSKJ1 treatment significantly suppressed cell proliferation and augmented chemotherapy-induced apoptosis, while exhibiting minimal cytotoxic effects when used as monotherapy. To explore the downstream regulatory pathways, we performed transcriptome analysis via RNA-seq followed by KEGG pathway enrichment analysis, which revealed that GSKJ1 treatment modulates key oncogenic signaling pathways. Integration of ChIP-seq data for H3K27me3 with transcriptomic profiles led to the identification of ERG3 as a potential downstream target. Protein interaction network analysis suggested that c-FOS is co-expressed with both KDM6B and ERG3. Co-immunoprecipitation (Co-IP) and Western blot (WB) assays confirmed the formation of a functional KDM6B/ERG3/c-FOS axis. Mechanistically, this axis regulates chemotherapy resistance by modulating apoptotic and ferroptotic pathways. Conclusion: Finally, in vivo experiments using patient-derived xenograft (PDX) models demonstrated that GSKJ1 effectively enhances the antitumor efficacy of chemotherapy in SCLC, providing compelling evidence for the clinical potential of targeting KDM6B to overcome chemoresistance.