ALDH18A1 silencing inhibits lung adenocarcinoma progression through mitochondrial dysfunction and PPAR signaling pathway activation.

Abstract

Background: Lung adenocarcinoma (LUAD) remains a prevalent malignant tumor characterized by a dismal prognosis. This study aimed to reveal potential mitochondria-related biomarkers and explore possible mechanisms.

Methods: Mitochondria-related differentially expressed genes (mitoDEGs) were identified by intersecting LUAD-associated DEGs with mitochondria-associated genes. Hub mitoDEGs were determined via protein-protein interaction (PPI) network analysis and machine learning. Aldehyde dehydrogenase 18 family member A1 (ALDH18A1) was silenced in LUAD cells to investigate its effects on proliferation, invasion, migration, and mitochondrial function. The potential involvement of the peroxisome proliferator-activated receptor (PPAR) signaling pathway in ALDH18A1-associated effects was evaluated in LUAD cells and tumor-bearing mice using the PPARγ antagonist GW9662.

Results: ALDH18A1 was identified as a hub mitoDEG and was highly expressed in LUAD.ALDH18A1 silencing promoted apoptosis, suppressed invasion and migration, and inhibited the proliferation of A549 cells. ALDH18A1 silencing induced mitochondrial dysfunction, as evidenced by elevated reactive oxygen species (ROS), diminished mitochondrial membrane potential, decreased ATP production, increased dynamin related protein 1 (DRP1) and mitofusin 2 (MFN2) expression, and decreased optic atrophy 1 (OPA1) in vitro and in vivo. ALDH18A1 silencing increased PPARγ and fatty acid-binding protein 4 (FABP4) expression, whereas GW9662 notably attenuated the antitumor and mitochondrial dysfunction-related effects of ALDH18A1 knockdown.

Conclusion: ALDH18A1 silencing inhibited LUAD progression and induced mitochondrial dysfunction, which may be partly associated with activation of the PPAR signaling pathway. These findings suggest that ALDH18A1 may serve as a candidate mitochondria-related molecular target for LUAD.