NLRC4 Acts as a Non‐Canonical Tumour Suppressor in Lung Adenocarcinoma by Inhibiting PI3K/AKT/mTOR Signalling to Induce Protective Autophagy
- 1Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine Qilu Hospital of Shandong University Jinan China
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.
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BibTeX
@article{zhang2026nlrc4,
title = {{NLRC4 Acts as a Non‐Canonical Tumour Suppressor in Lung Adenocarcinoma by Inhibiting PI3K/AKT/mTOR Signalling to Induce Protective Autophagy}},
author = {Yuxin Zhang and Shuangteng Liu and Rui Li and Mengyu Zhang and Guang Yang and Xinmiao Zhu and Yiqing Qu},
journal = {Journal of Cellular and Molecular Medicine},
year = {2026},
month = oct,
doi = {10.1111/jcmm.71420},
url = {https://doi.org/10.1111/jcmm.71420},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - NLRC4 Acts as a Non‐Canonical Tumour Suppressor in Lung Adenocarcinoma by Inhibiting PI3K/AKT/mTOR Signalling to Induce Protective Autophagy
AU - Yuxin Zhang
AU - Shuangteng Liu
AU - Rui Li
AU - Mengyu Zhang
AU - Guang Yang
AU - Xinmiao Zhu
AU - Yiqing Qu
PY - 2026
DA - 2026/10/01
JO - Journal of Cellular and Molecular Medicine
DO - 10.1111/jcmm.71420
UR - https://doi.org/10.1111/jcmm.71420
AB - 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.
SN - 1582-1838
SN - 1582-4934
ER -