Identification of MORC2 via bioinformatics and machine learning reveals its transcriptional activation by PAX2 in NSCLC malignancy

Background Non-small cell lung cancer (NSCLC) represents the top contributor to cancer-associated deaths globally, and its suboptimal clinical outcomes are linked to late-stage detection and acquired resistance to existing therapies. Microrchidia family CW-type zinc finger 2 (MORC2) has been found to exhibit oncogenic potential in NSCLC, but its transcriptional regulatory mechanisms and role in glycolytic reprogramming remain unclear. Results As a key gene, MORC2 was found to be overexpressed in NSCLC and linked to poor prognosis. MORC2 silencing impaired cell proliferation, stemness, and invasion, diminished glycolysis, and enhanced apoptosis. PAX2 was confirmed to directly transcriptionally activate MORC2; overexpression of MORC2 reversed the defects in malignant phenotypes induced by PAX2 knockdown. In vivo , depletion of PAX2 suppressed tumor growth, which was partially rescued by MORC2 overexpression. Conclusions The PAX2/MORC2 axis was demonstrated to drive NSCLC malignancy, supporting MORC2 as a potential prognostic marker and therapeutic target for NSCLC.