FOSL1 promotes homologous recombination repair and camptothecin resistance via TCOF1-mediated ribosome biogenesis in non-small cell lung cancer

Background: Camptothecin (CPT) and its derivatives are important chemotherapeutic agents; however, intrinsic and acquired tolerance frequently limits their long-term efficacy. This study aimed to identify key transcriptional regulators of CPT responsiveness in non-small cell lung Cancer (NSCLC) and to elucidate the underlying molecular mechanisms.

Methods: Single-cell RNA sequencing-based transcriptomic profiling, integrated with bulk RNA-seq, was used to prioritize CPT-responsive transcriptional programs and nominate candidate regulators. Functional roles were validated using gain- and loss-of-function approaches in NSCLC cell lines. DNA damage repair, ribosome biogenesis, and translational activity were assessed using molecular and reporter assays. Pharmacological inhibition of ribosome biogenesis was evaluated using the RNA polymerase I inhibitor BMH-21, and therapeutic relevance was further examined in xenograft models.

Results: We identified FOSL1 as a CPT-responsive transcription factor that was associated with poor prognosis in lung adenocarcinoma. CPT treatment induced FOSL1 expression and nuclear accumulation, whereas FOSL1 depletion markedly enhanced CPT-induced cytotoxicity. Mechanistically, loss of FOSL1 resulted in persistent DNA damage accumulation and selective impairment of homologous recombination (HR) repair. FOSL1 sustained HR repair indirectly by promoting ribosome biogenesis through transcriptional activation of TCOF1. Pharmacological inhibition of ribosome biogenesis phenocopied FOSL1 depletion and significantly potentiated CPT efficacy both in vitro and in vivo.

Conclusion: Our study defines a FOSL1-TCOF1-ribosome axis that promotes CPT tolerance in NSCLC by maintaining HR repair. These findings provide a rationale for targeting ribosome biogenesis to enhance CPT-based treatment and highlight coordinated regulation of transcription, protein synthesis, and DNA repair under chemotherapeutic stress.