Evaluating the causal role of LEPR signaling in 16 cancers: A drug-target Mendelian randomization study.

The leptin receptor (LEPR) serves as a central regulator of energy balance and metabolic homeostasis, with growing interest in its pleiotropic roles in cancer. However, existing evidence on its oncogenic function remains ambiguous, with studies reporting both tumor-promoting and tumor-suppressive effects across different contexts. This duality complicates the interpretation of LEPR's precise role in carcinogenesis. Moreover, conventional observational studies are inherently limited by residual confounding and reverse causality, leaving the causal relationship between LEPR signaling and site-specific cancer risk unresolved. To address this, we performed a drug-target Mendelian randomization analysis to assess the causal effect of genetically proxied LEPR activity on 16 such cancers. We selected cis-expression quantitative trait loci (cis-eQTLs) associated with LEPR expression in blood from the eQTLGen Consortium (n = 31,684) as instrumental variables, and harmonized them with summary-level genome-wide association study data for cancers from the FinnGen R12 release. Among the 16 evaluated malignancies, our primary finding demonstrated that genetically elevated LEPR signaling was significantly associated with a lower risk of pancreatic cancer (odds ratio = 0.91; 95% CI: 0.87-0.96; P = 3.93 × 10-4). This association withstood Bonferroni correction and was consistent across sensitivity analyses. Suggestive inverse associations were also observed for lung squamous cell carcinoma, gastric cancer, and breast cancer subtypes (P <.05), whereas no significant causal links were detected for the remaining ten cancers. No significant heterogeneity or horizontal pleiotropy was detected. In summary, this drug-target Mendelian randomization study provides concise genetic evidence supporting a protective role of LEPR signaling specifically in pancreatic cancer, with suggestive effects in several other malignancies. These findings inform the pathophysiological understanding of leptin in cancer and highlight the relevance of LEPR-modulating strategies for safety assessment in oncology. Limitations include the use of blood-derived eQTLs and restriction to European ancestry, which may affect generalizability.