NINJ1 promotes lung adenocarcinoma progression via activation of the PI3K-AKT signaling axis and suppression of cell death pathways

Abstract Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, and current therapeutic options often fail to yield sustained responses. Ninjurin1 (NINJ1), a transmembrane protein implicated in plasma membrane rupture during lytic cell death, has recently emerged as a potential antitumor target, yet its role in LUAD pathogenesis remains poorly defined. Here, we comprehensively investigated the functional relevance and mechanistic regulation of NINJ1 in LUAD progression. We observed elevated NINJ1 expression in human LUAD tissues and cell lines. Genetic ablation of NINJ1 or pharmacological inhibition using NINJ1-derived short peptides significantly impaired tumor cell proliferation and migration, enhanced sensitivity to chemotherapeutic agents, and suppressed the growth of human iPSC-derived LUAD organoids and xenografted tumors in vivo. Mechanistically, NINJ1 was found to directly associate with PI3K, thereby activating the downstream AKT signaling pathway. Loss of NINJ1 led to widespread transcriptional dysregulation, affecting gene networks involved in cell cycle progression, epithelial-mesenchymal transition (EMT), and inflammatory responses. Functionally, NINJ1 deficiency induced G1 phase arrest, mitochondrial dysfunction, and increased susceptibility to cell death. These findings identify NINJ1 as a key molecular driver of LUAD malignancy and highlight its potential as a promising therapeutic target for lung cancer.