biostudies-literatureTang YNational Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)431https://www.ebi.ac.uk/biostudies/studies/S-EPMC11906602biostudies-literatureUnknown8(1)Our study elucidates the role of FOXP1 in chemoresistance in small cell lung cancer(SCLC). FOXP1 enhances chemoresistance by regulating SP8 expression through its super-enhancer (SP8-SE), with SP8 mediating resistance via the homologous recombination repair (HRR) pathway. We also discovered that FOXP1 forms punctate nuclear structures indicative of liquid-liquid phase separation, crucial for its transcriptional regulation. Targeting the FOXP1-SP8-HR axis with BRD4 and PARP inhibitors showed synergistic effects in reducing tumor growth in vitro and in patient-derived xenograft models. These findings identify FOXP1 as a critical mediator and marker of chemoresistance in SCLC, providing a foundation for developing targeted therapies to overcome this resistance.Communications biologyTargeting FOXP1 phase separation in small cell lung cancer mechanisms of chemotherapy resistance.PMC11906602,82172769Sun LXiong YGuo LHu YWang QChen YWang YZhou XTang YNiu YXu YfalseTargeting FOXP1 phase separation in small cell lung cancer mechanisms of chemotherapy resistance.Our study elucidates the role of FOXP1 in chemoresistance in small cell lung cancer(SCLC). FOXP1 enhances chemoresistance by regulating SP8 expression through its super-enhancer (SP8-SE), with SP8 mediating resistance via the homologous recombination repair (HRR) pathway. We also discovered that FOXP1 forms punctate nuclear structures indicative of liquid-liquid phase separation, crucial for its transcriptional regulation. Targeting the FOXP1-SP8-HR axis with BRD4 and PARP inhibitors showed synergistic effects in reducing tumor growth in vitro and in patient-derived xenograft models. These findings identify FOXP1 as a critical mediator and marker of chemoresistance in SCLC, providing a foundation for developing targeted therapies to overcome this resistance.2025-01-01T00:00:00Z2025 Mar2026-05-29T17:03:37.893Z2026-04-08T05:27:39.186ZS-EPMC119066024008253810.1038/s42003-025-07804-7