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VDAC1 may contribute to lung adenocarcinoma progression using PI3K/AKT/mTOR signaling and EMT
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DOI：10.1186/s12931-026-03867-0.png)
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Abstract
En 中文
Lung adenocarcinoma (LUAD) is a highly prevalent and lethal malignancy worldwide. Its pronounced heterogeneity and limited therapeutic options present substantial clinical challenges. Mitochondria and programmed cell death (PCD) markedly regulate tumor development, but their precise roles in LUAD pathogenesis remain unclear. This study aims to identify key genes associated with mitochondrial function and PCD, construct a prognostic model for LUAD, and investigate the prognostic significance and potential protumorigenic mechanisms of VDAC1 in this context. We integrated single‑cell RNA‑seq (GSE131907) with bulk transcriptomic data from TCGA‑LUAD and GEO. A LASSO‑Cox regression‑based prognostic signature was built and validated. Single‑cell subclustering, pseudotime trajectory, and cell–cell communication analyses were performed to dissect VDAC1’s cell‑type‑specific roles. In vitro functional assays (CCK‑8, colony formation, Transwell, flow cytometry, Western blot) and rescue experiments with the ROS scavenger NAC were conducted in A549 and H1975 cells. Co‑immunoprecipitation was used to examine the VDAC1–AKT interaction. A five‑gene prognostic signature (ACSL1, VDAC1, CYCS, GLS2, MPV17L) was established and validated, effectively stratifying patients into high‑ and low‑risk groups with distinct survival outcomes. Single‑cell resolution revealed that VDAC1 is highly enriched in malignant epithelial cells, inflammatory cancer‑associated fibroblasts, and immunosuppressive M2 macrophages, where it drives proliferation, extracellular matrix (ECM) remodeling, and lipid metabolic reprogramming, respectively. VDAC1 was markedly overexpressed in LUAD tissues and cell lines; high VDAC1 expression independently correlated with advanced TNM stage, lymph node metastasis, and poor prognosis. VDAC1 knockdown suppressed proliferation, migration, invasion, and EMT, induced G0/G1 arrest and apoptosis, decreased ATP production and oxygen consumption rates, and increased ROS levels. Mechanistically, VDAC1 activated the PI3K/AKT/mTOR pathway and directly interacted with AKT (co‑immunoprecipitation). NAC‑mediated ROS scavenging only partially rescued the si‑VDAC1‑induced suppression of signaling, EMT, and proliferation, indicating a ROS‑dependent mechanism complemented by a ROS‑independent direct interaction. Additionally, VDAC1 expression was negatively correlated with most antitumor immune cells and positively associated with immune checkpoint molecules (e.g., PD‑L1), suggesting an immunosuppressive microenvironment. We present a novel mitochondria‑ and PCD‑related five‑gene prognostic model for LUAD. VDAC1 is identified as a key oncogenic driver that promotes LUAD progression through dual mechanisms: ROS‑mediated activation of PI3K/AKT/mTOR signaling and direct physical interaction with AKT, leading to EMT, metabolic reprogramming, and immunosuppressive microenvironment remodeling. These findings establish that VDAC1 is a promising prognostic biomarker and a potential therapeutic target in LUAD.
Keywords:
Lung adenocarcinoma
VDAC1
Mitochondria
Programmed cell death
Prognostic model
Tumor microenvironment
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803
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1.5W
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