RACGAP1 defines a malignant proliferative niche and represents a therapeutic vulnerability in lung adenocarcinoma.

Background: The clinical management of lung adenocarcinoma (LUAD) is compromised by post-surgical recurrence and therapeutic resistance, underscoring the urgent need to uncover actionable therapeutic vulnerabilities. By integrating human genetics with multi-omics profiling and experimental validation, this study aims to systematically uncover critical molecular mediators of LUAD and delineate their therapeutic potential. Methods: We implemented a multi-modal framework to identify and characterize causal LUAD therapeutic targets. We used two-sample Mendelian randomization (2SMR) to identify plasma proteins that are causally linked to LUAD risk. The lead candidate was then investigated using multi-omics to delineate its clinical relevance, cellular drivers, and tumor microenvironment. Oncogenic mechanisms were subsequently interrogated through functional experiments in LUAD models. Results: Our unbiased genetic screen identified Rac GTPase-activating protein 1 (RACGAP1) as a high-confidence causal risk factor for LUAD. Clinically, elevated RACGAP1 expression served as a robust, independent prognostic biomarker associated with poor survival across multiple cohorts. Single-cell profiling revealed that Conclusions: This study presents genetic evidence supportive of a causal contribution of RACGAP1 to LUAD, highlighting it as a promising prognostic biomarker and candidate therapeutic target. By delineating a RACGAP1-driven axis that coordinates survival signaling and suppresses tumor surveillance, our findings highlight RACGAP1 as a promising therapeutic target for novel adjuvant strategies.