Study on the mechanism of PSENEN in modulating cisplatin resistance in NSCLC through stromal cell interactions

Lung cancer remains a leading cause of cancer-related mortality worldwide. Chemotherapy, including cisplatin, plays a pivotal role in its treatment; however, the development of cisplatin resistance presents a major clinical challenge. The PSENEN gene, which encodes a regulatory protein, is overexpressed in numerous malignancies. This study explores the role of PSENEN in mediating cisplatin resistance in non-small cell lung cancer (NSCLC). RNA sequencing revealed significant upregulation of PSENEN in cisplatin-resistant A549/DDP cells. Functionally, PSENEN inhibition reversed cisplatin resistance, inhibited cell proliferation and metastasis, and enhanced programmed cell death in A549/DDP cells. Single-cell RNA sequencing indicated that PSENEN was expressed in both cancer and stromal cells. Further functional studies suggested that PSENEN regulates chemoresistance through interactions within the stromal microenvironment. Differentially expressed protein analysis (DIA) of stromal cell supernatants, coupled with functional assays, identified PPIB as a key mediator of PSENEN's effect on lung cancer cell drug resistance via stromal signaling. In vivo, pharmacological inhibition of PSENEN significantly suppressed subcutaneous tumor growth. Additionally, analysis of the immune microenvironment revealed a strong correlation between PSENEN expression and the infiltration of multiple immune cell types. Multiple immunofluorescence and immunohistochemistry validation confirmed that PSENEN is positively correlated with CD56 and PD-1, suggesting its potential application value in immunotherapy.