LEPR Contributes to Lung Squamous Cell Carcinoma: Insights From Mendelian Randomization and Experimental Studies

Background The involvement of certain adipokines link to carcinogenesis, development, and prognosis. However, the roles of adipokines in lung cancer and its histological subtypes remains indistinct. Therefore, the aims of this study are to explore the causal relationship between adipokines and lung cancers. Methods Summary-level data for exposures (six adipokines) and outcomes (lung cancer and its histological subtypes) were collected from the IEU OpenGWAS, International Lung Cancer Consortium (ILCCO) and lectures. Two-sample mendelian randomization (MR) was conducted to estimate the causality by employing single nucleotide polymorphisms (SNPs) as instrument variables (IVs). Human tissue microarray and immunohistochemistry (IHC) analysis validated the adipokines expression. Functional effects of LEPR in LUSC were assessed in vitro using NCI-H2170 and SK-MES-1 cell lines via siRNA-mediated knockdown, followed by assays for cell proliferation, invasion, and apoptosis. Results Leptin receptor (LEPR) was associated with risk of lung squamous cell carcinoma (LUSC, OR: 1.05, 95% CI: 1.01-1.08; P < 0.0125), and no other adipokines associated with lung cancer and its histological subtypes (P > 0.05). Experimental results revealed that high expression of LEPR in LUSC tumor samples compared to adjacent normal samples, and associated with unfavorable survival status. In vitro , LEPR knockdown significantly inhibited proliferation and invasion while promoting apoptosis in LUSC cells. Conclusion These findings suggest that LEPR may play a critical role in the development and progression of LUSC, providing a potential target for therapeutic intervention.