Non-small cell lung cancer (NSCLC) is one of the leading cancer killers. Apigenin (Api) and Naringenin (Nar) are natural bioactive substances obtained in various vegetables and fruits, possessing anti-tumor effects across multiple studies. This study investigated the latent synergistic antiproliferative functions of Api and Nar in A549 and H1299 NSCLC cells. Cell viability was determined after incubating with different concentrations of Api, Nar, or the combination of Api and Nar (CoAN) for 24 h. Analysis using the CompuSyn software revealed that the CI value of each combined dose was < 1, depicting that the two drugs had a synergistic inhibitory effect. The CoAN (A:N = 3:2) group with the lowest CI value was selected for subsequent experiments. The IC₅₀ of CoAN (A:N = 3:2) was used to determine the cell cycle, the expression ratio of Bax to Bcl2, Caspase 3 activity, and mitochondrial function to assess oxidative stress and apoptosis. The results established that CoAN treatment caused significant cytotoxicity with cell cycle arrest at G2/M phases. Furthermore, CoAN significantly enhanced mitochondria dysfunction, elevated oxidative stress, and activated the apoptotic pathway versus Api or Nar alone groups. Thus, the CoAN chemotherapy approach is promising and deserves further research.

Radiotherapy (RT) is one of the most effective cancer treatments. However, successful radiation protection for normal tissue is a clinical challenge. Our previous study observed that MitoQ, a mitochondria-targeted antioxidant, was adsorbed to the inner mitochondrial membrane and remained the cationic moiety in the intermembrane space. The positive charges in MitoQ restrained the activity of respiratory chain complexes and decreased proton production. Therefore, a pseudo-mitochondrial membrane potential (PMMP) was developed via maintenance of exogenous positive charges. This study identified that PMMP constructed by MitoQ could effectively inhibit mitochondrial respiration within normal cells, disrupt energy metabolism, and activate adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling to induce autophagy. As such, it could not lead to starvation-induced autophagy among tumor cells due to the different energy phenotypes between normal and tumor cells (normal cells depend on mitochondrial respiration for energy supply, while tumor cells rely on aerobic glycolysis). Therefore, we successfully protected the normal cells from radiation-induced damage without affecting the tumor-killing efficacy of radiation by utilizing selective autophagy. MitoQ-constructed PMMP provides a new therapeutic strategy for specific radiation protection.

Mitochondria are double-membrane organelles that are involved in energy production, apoptosis, and signaling in eukaryotic cells. Several studies conducted over the past decades have correlated mitochondrial dysfunction with various diseases, including cerebral ischemia, myocardial ischemia-reperfusion, and cancer. Mitochondrial transplantation entails importing intact mitochondria from healthy tissues into diseased tissues with damaged mitochondria to rescue the injured cells. In this review, the different mitochondrial transplantation techniques and their clinical applications have been discussed. In addition, the challenges and future directions pertaining to mitochondrial transplantation and its potential in the treatment of diseases with defective mitochondria have been summarized.

Cancer-associated fibroblasts (CAFs), as the “architect” of the immune microenvironment in lung cancer, play a multidimensional role in tumor progression and immune regulation. In this review, we summarize the heterogeneity of the origin and the molecular phenotype of CAFs in lung cancer, and explore the complex interactions between CAFs and multiple components of the tumor microenvironment, including the regulatory relationships with innate immune cells (e.g., tumor-associated macrophages, tumor-associated neutrophils), adaptive immune cells (e.g., T cells), and extracellular matrix (ECM). CAFs significantly influence tumor progression and immunomodulation through the secretion of cytokines, remodeling of the ECM, and the regulation of immune cell function significantly affects the immune escape and treatment resistance of tumors. In addition, this review also deeply explored the synergistic regulatory relationship between CAF and radiotherapy, revealing the key role of CAF in radiotherapy-induced remodeling of the immune microenvironment, which provides a new perspective for optimizing the comprehensive treatment strategy of lung cancer. By comprehensively analyzing the multidimensional roles of CAF and its interaction with radiotherapy, this review aims to provide a theoretical basis for the precise regulation of the immune microenvironment and clinical treatment of lung cancer.

Increased stemness of cancer cells exacerbates radioresistance, thereby greatly limiting the efficacy of radiotherapy. In order to study the changes in cancer cell stemness during radiotherapy, we established a radioresistance model of human non-small cell lung cancer A549 cells and obtained A549 radioresistant cells (A549-RR). We sampled the cells at different time points during the modeling process and investigated the heterogeneity of each group of cells using single-cell sequencing. Cells in the early stages of fractionated irradiation were found to be significantly up-regulated in stemness, and a subpopulation of cells producing this response was screened and referred to as “radiation-induced stemness-responsive cancer cells”. They were undergoing stemness response, energy metabolism reprogramming, and progressively differentiating into cells with more diverse and malignant phenotypes in order to attenuate the killing effect of radiation. Furthermore, we demonstrated that such responses might be driven by the activation of the EGFR-Hippo signaling pathway axis, which also plays a crucial role in the development of radioresistance. Our study reveals the dynamic evolution of cell subpopulation in cancer cells during fractionated radiotherapy; the early stage of irradiation can determine the destiny of the radiation-induced stemness-responsive cancer cells. The activation of stemness-like phenotypes during the development of radioresistance is not the result of dose accumulation but occurs during the early stage of radiotherapy with relatively low-dose irradiation. The degree of the radiation-induced stemness response of cancer cells mediated by the EGFR-Hippo signaling pathway might be a potential predictor of the efficacy of radiotherapy and the development of radioresistance.