Targeting the NR5A1-KISS1R-EMT axis with a small-molecule inhibitor suppresses lung adenocarcinoma progression and metastasis.

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, with an urgent need for novel therapeutic targets beyond the established driver mutations. Here, we identify the orphan nuclear receptor NR5A1 (Steroidogenic Factor-1) as an oncogenic factor in LUAD. Through integrated bioinformatic analyses, we discovered that NR5A1 is significantly overexpressed in LUAD tumors and that its high expression correlates strongly with poor patient prognosis. We demonstrate that pharmacological inhibition of NR5A1 with the small-molecule inhibitor SID 7969543, or genetic ablation of NR5A1, potently suppresses LUAD cell proliferation, invasion, and clonogenicity in vitro. In vivo, SID 7969543 treatment markedly inhibited tumor growth and angiogenesis in both chick chorioallantoic membrane and orthotopic mouse models of LUAD. Mechanistically, transcriptomic profiling revealed that NR5A1 signaling converges on the regulation of the Epithelial-Mesenchymal Transition (EMT), a key program for metastasis. We identified the Kisspeptin Receptor (KISS1R) as a direct transcriptional target of NR5A1 and a critical downstream effector. We show that NR5A1-mediated activation of KISS1R is essential for maintaining the mesenchymal phenotype and that depletion of KISS1R phenocopies NR5A1 inhibition. Crucially, overexpression of KISS1R conferred resistance to the anti-tumor effects of SID 7969543, confirming its pivotal role in the signaling cascade. Collectively, our findings uncover a previously uncharacterized NR5A1-KISS1R-EMT signaling axis that drives LUAD progression and establish NR5A1 as a promising, druggable target. This work provides a robust preclinical rationale for the development of NR5A1-targeted therapies for the treatment of lung adenocarcinoma.