ROR? drives non-small cell lung cancer progression by upregulating the NGF signalling

Lung cancer remains one of the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) representing the most common subtype—highlighting the critical need for novel therapeutic approaches. Here, we identify the retinoic acid receptor-related orphan receptor gamma (ROR?) as a key driver of NSCLC progression. Integrative bioinformatics and immunohistochemical analysis revealed that ROR? is highly expressed in NSCLC tissues and that its expression correlates with poor patient prognosis. Functionally, elevated ROR? significantly enhanced the proliferation, migration, and invasion capabilities of NSCLC cells. Conversely, treatment with the ROR? antagonist or genetic silencing of ROR? potently suppressed these malignant phenotypes both in vitro and in vivo. Mechanistically, ROR? directly binds to the promoter region of NGF, stimulates NGF gene transcription, and thereby promotes NSCLC progression. ROR? antagonists suppress NGF expression and inhibit its downstream signalling pathways, whereas exogenous NGF supplementation or overexpression of NGF notably reverses the inhibitory effects of ROR? antagonists on NSCLC cells. Taken together, these results establish ROR? as a critical regulator of NSCLC and a promising therapeutic target for NSCLC treatment. Overall design: H157 cells were treated with vehicle (DMSO) or W6134 (2.5 µM) for 48 hours before total RNA extraction. The extraction steps of total RNA were according to the manufacturer's protocol of the Vazyme Super FastPure Cell RNA Isolation Kit (Vazyme Biotech, Nanjing, China). Transcriptomic sequencing of RNA-seq libraries were validated through MGISEQ2000 machine (BGI Tech, China). Enrichment analysis of co-downregulated genes (expression changes of = 1.5-fold) in both cell lines following W6134 treatment was performed using R (v4.2.1), with the most significantly enriched pathways visualized via volcano plots (considering p adjust (FDR) < 0.05 as statistically significant).