Mitochondrial hyperfunction is implicated in promoting non-small cell lung cancer (NSCLC) cell growth. TIMM23 (translocase of inner mitochondrial membrane 23) is a core component of the mitochondrial import machinery, facilitating the translocation of proteins across the inner mitochondrial membrane into the matrix. Its expression and potential functions in NSCLC were tested. Comprehensive bioinformatic analysis revealed a strong correlation between TIMM23 overexpression and adverse clinical outcomes in NSCLC patients. Single-cell RNA sequencing data further corroborated these findings, demonstrating elevated TIMM23 expression within the cancer cells of NSCLC mass. Subsequent experimental validation confirmed significantly increased TIMM23 mRNA and protein levels in locally-treated NSCLC tissues compared to matched normal lung tissues. Moreover, TIMM23 expression was consistently elevated across multiple primary/established NSCLC cells. Silencing or ablation of TIMM23 via shRNA or CRISPR/Cas9 in NSCLC cells resulted in impaired mitochondrial function, characterized by reduced complex I activity, ATP depletion, mitochondrial membrane potential dissipation, oxidative stress, and lipid peroxidation. These mitochondrial perturbations coincided with attenuated cell viability, proliferation, and migratory capacity, and concomitant induction of apoptosis. Conversely, ectopic overexpression of TIMM23 significantly enhanced mitochondrial complex I activity and ATP production, promoting NSCLC cell proliferation and motility. In vivo, intratumoral delivery of a TIMM23 shRNA-expressing adeno-associated virus significantly suppressed the growth of subcutaneous NSCLC xenografts in nude mice. Subsequent analysis of tumor tissues revealed depleted TIMM23 expression, ATP reduction, oxidative damage, proliferative arrest, and apoptotic induction. Collectively, these findings establish TIMM23 as a critical pro-tumorigenic factor in NSCLC, highlighting its potential as a prognostic biomarker and therapeutic target.

Objectives: Malignant pleural mesothelioma is a rare and aggressive thoracic tumor with a poor prognosis, wherein distant metastasis is associated with the lowest survival rates. It is imperative and emergent to construct nomograms based on risk factors and prognostic factors for distant metastasis in patients with malignant pleural mesothelioma. Methods: We extracted data for the duration between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database and randomly categorized the patients into the training (70%) and validation (30%) cohorts. Risk factors for distant metastasis in patients with malignant pleural mesothelioma were identified using univariate and multivariate logistic regression analyses, and prognostic factors for patients with distant metastasis were determined using univariate and multivariate Cox regression analyses. Two nomograms were established based on the training cohort and evaluated using the validation cohort. The C-index, receiver operating characteristic curve, calibration curve, and decision curve analysis were used to assess the performance of the two nomograms. Results: In total, 2056 primary malignant pleural mesothelioma patients were included, and 341 patients were initially diagnosed with metastatic malignant pleural mesothelioma. Histology, laterality, grade, tumor stage, and node stage were independent risk factors for distant metastasis in patients with malignant pleural mesothelioma. Chemotherapy and metastasis to the lung, bone, and brain were independent prognostic factors for patients with malignant pleural mesothelioma and distant metastasis. The C-index values of the risk nomogram in the training and validation cohorts were 0.723 and 0.782, respectively. The C-index values of the prognostic nomogram in the training and validation cohorts were 0.678 and 0.712, respectively. The receiver operating characteristic curves, calibration curves, and decision curve analysis also demonstrated good predictive performance for the two nomograms in the training and validation cohorts. Conclusions: Nomograms are useful and reliable tools for predicting distant metastatic risk in patients with malignant pleural mesothelioma and overall survival in patients with malignant pleural mesothelioma who had distant metastasis. These nomograms can provide strong references to clinicians to facilitate clinical decisions.