NLRC 4 Acts as a Non‐Canonical Tumour Suppressor in Lung Adenocarcinoma by Inhibiting PI 3 K / Yuxin Zhang, Shuangteng Liu, Rui Li, Mengyu Zhang, Guang Yang, Xinmiao Zhu, Yiqing Qu

ABSTRACT

Autophagy plays complex, context‐dependent roles in lung adenocarcinoma (LUAD), but the upstream molecular drivers that govern this process remain elusive. NLRC4 is classically defined as a pyroptosis‐inducing inflammasome sensor, yet its non‐canonical, tumour‐intrinsic function in LUAD progression remains largely unexplored. Through multi‐omics screening and prognostic modelling across TCGA and GEO datasets, we identified NLRC4 as a critical autophagy‐associated protective factor, which was validated in an institutional cohort of paired LUAD tissues. In vitro and in vivo assays, autophagic flux monitoring, reciprocal co‐immunoprecipitation and genetic rescue experiments were employed to elucidate the underlying mechanism. NLRC4 protein was markedly downregulated in LUAD tissues alongside the tumour suppressor PTEN, correlating with advanced TNM stage and poor overall survival. Functionally, restoring NLRC4 expression inhibited LUAD cell proliferation, motility, invasion and epithelial–mesenchymal transition in vitro, whereas NLRC4 depletion accelerated xenograft tumour growth in vivo. Crucially, NLRC4 selectively stimulated complete autophagic flux without triggering Caspase‐1/Gasdermin cleavage or lytic pyroptotic death. Mechanistically, NLRC4 physically interacted with NFKB1 (p105/p50) in a tumour‐selective manner, relieving NF‐κB‐mediated transcriptional repression of PTEN. This restored PTEN expression, thereby tonically dampening the PI3K/AKT/mTOR signalling cascade. Genetic blockade of autophagy (siATG5) or PTEN ablation largely reversed the tumour‐suppressive effects of NLRC4, confirming the functional dependency on the PTEN–autophagy axis. Our study establishes a non‐canonical, tumour‐intrinsic role for NLRC4 in restraining LUAD progression via the PI3K/AKT/mTOR axis to induce protective autophagy, positioning it as a promising prognostic biomarker and potential therapeutic target.