Search

Abstract Background Postoperative radiotherapy (PORT) is crucial for patients with thoracic locally advanced esophageal squamous cell carcinoma (LA-ESCC, pT3-4aN0-3M0) following esophagectomy. However, the appropriate radiation volume has not been well established. This study aimed to determine the optimal PORT volume for LA-ESCC patients. Methods LA-ESCC patients post-esophagectomy were randomly assigned to either the large-field irradiation (LFI, primary lesion and lymph node tumor bed plus elective nodal irradiation) group or the small-field irradiation (SFI, primary lesion and lymph node tumor bed alone) group. Stratification was based on T stage and the number of lymph node metastases. The primary endpoint was disease-free survival (DFS), while the secondary endpoints included overall survival (OS), adverse events, and patterns of initial failure. Results A total of 401 patients were randomly assigned to the intention-to-treat analysis(LFI group, n = 210; SFI group, n = 191). The median DFS of patients in the LFI group was 47.9 months and 48.1 months in the SFI group (HR = 0.87, 95%CI, 0.65 to 1.16; p = 0.32). The estimated one-year and three-year OS rates were 89.2% and 63.2% for patients in the LFI group, compared to 86.6% and 60.7% for the SFI group, respectively. The difference of OS between the two groups was not significant (HR = 0.86, 95%CI, 0.63 to 1.16; p = 0.35). Fewer patients in the LFI group experienced locoregional recurrence compared to the SFI group (12.9% vs 20.4%, p = 0.013). Additionally, locoregional recurrence-free survival of the LFI group was significantly longer than that of SFI group (HR = 0.54, 95%CI, 0.34–0.87; p = 0.01). The most common toxicity was grade 2 esophagitis, observed in 22.9% of the LFI group and 16.8% of the SFI group. Grade 3 adverse events occurred in 6.7% of the LFI group and 2.6% of the SFI group. No grade 4 or 5 toxicities were observed. Adverse events did not significantly differ between the two groups. Conclusions Postoperative radiotherapy, with the specified radiation volume shows encouraging survival outcomes that are comparable to those of neoadjuvant chemoradiotherapy in patients with thoracic LA-ESCC. Both postoperative irradiation fields were found to be feasible and safe.

Abstract Background Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields. Methods This trial compared two aspects of radiation treatment, total dose and field, using a two‐by‐two factorial design. The high‐dose (HD) group received 59.4 Gy radiation, and the standard‐dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression‐free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field. Results The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80‐1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82–1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72–1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons. Conclusions IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.

Sorghum faces significant production challenges due to drought stress. Melatonin has been demonstrated to play a crucial role in coping with stresses in plants. This study investigated the effect of exogenous melatonin on the sorghum seedling growth, photosynthetic capacity, and antioxidant system under drought stress. The results indicated that drought stress inhibited the growth of sorghum seedlings by a marked reduction in leaf relative water content, along with a significant increase in both malondialdehyde and hydrogen peroxide content. The drought stress also led to a significant diminution in chlorophyll contents, thereby curtailing the capacity for light energy capture. Furthermore, the efficiency of the photosynthetic electron transport chain was adversely impacted. However, the application of exogenous melatonin notably mitigated the adverse effects on sorghum seedlings under the drought stress. Additionally, it stimulated an elevation in the photosynthetic rate and a decrease in non-photochemical quenching. The exogenous melatonin also facilitated the preservation of the chloroplast ultra-structure and boosted the activity of antioxidant enzymes and the content of non-enzymatic antioxidants. Cluster heat maps and principal component analysis further revealed significant correlations among various parameters under different treatment conditions. These results highlight melatonin’s role in improving sorghum’s drought tolerance, which is beneficial for agricultural management.

Abstract The incidence and mortality rate of esophageal cancer (EC) are higher worldwide. Exosomes are nanoscale vesicles derived from various types of cells, exhibiting a stable presence in bodily fluids, and contain a plethora of bioactive components including proteins, DNA, and RNA. Exosomes can mediate cell-to-cell communication and signaling. Numerous studies conducted both domestically and internationally have indicated the significant involvement of exosomes in tumor development and their potential as novel diagnostic and prognostic biomarkers for liquid biopsy. This review seeks to consolidate the role of exosomes and bioactive substances in the progression of EC and elaborate on the opportunities and challenges associated with the clinical application of exosomes in EC.

Abstract Circular RNAs (circRNAs) possess unique biological properties and distribution characteristics that enable a variety of biological functions. N6-methyladenosine (m6A), a prevalent epigenetic modification in organisms, is regulated by factors including methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). These factors play critical roles in various pathophysiological processes. There is growing evidence that m6A modifications are common within circRNAs, affecting their synthesis, translation, translocation, degradation, and stability. Additionally, circRNAs regulate biological processes that influence m6A modifications. This review explores the metabolism and functions of m6A modifications and circRNAs, their interactions, and their specific regulatory mechanisms in different tumors, offering insights into m6A-circRNA interaction in cancer.

IntroductionSorghum (Sorghum bicolor L.) can withstand drought and heat stress and efficiently utilize water and nutrients. However, the underlying mechanism of its tolerance to low-nitrogen (N) stress remains poorly understood.Materials and methodsThis study assessed low-N tolerance in 100 sorghum-inbred lines and identified those with exceptional resilience. Principal component analysis, Pearson’s correlation, and Y value analysis were used to examine various seedling growth metrics, including plant and root dimensions, biomass, chlorophyll content, root N content, shoot N content, and root/shoot ratio.Results and discussionThe genotypes were categorized into four distinct groups based on their respective Y values, revealing a spectrum from highly tolerant to sensitive. Low-N-tolerant sorghum lines maintained higher photosynthetic rates and exhibited increased enzymatic activities linked to carbon and N metabolism in the leaves and roots. Furthermore, low-N-tolerant genotypes had higher levels of key amino acids, including cystine, glycine, histidine, isoleucine, leucine, phenylalanine, threonine, and tyrosine, indicating a robust internal metabolic response to N deficiency.ConclusionThis study provides a comprehensive and reliable approach for the evaluation of sorghum tolerance to low-N environments, sheds light on its morphological and physiological adaptations, and provides valuable insights for future breeding programs and agricultural practices.

Abstract Radiation therapy is an important tool for malignant tumors, and its tolerance needs to be addressed. In recent years, several studies have shown that regulators of aberrant m6A methylation play an important role in the formation, development and invasion and metastasis of tumors. A large number of studies have confirmed aberrant m6A methylation as a new target for tumour therapy, but research on whether it can play a role in tumor sensitivity to radiotherapy has not been extensive and thorough enough. Recent studies have shown that all three major enzymes of m6A methylation have significant roles in radioresistance, and that the enzymes that play a role differ in different tumor types and by different mechanisms, including regulating tumor cell stemness, affecting DNA damage and repair, and controlling the cell cycle. Therefore, elucidating the mechanisms of m6A methylation in the radiotherapy of malignant tumors is essential to counteract radioresistance, improve the efficacy of radiotherapy, and even propose targeted treatment plans for specific tumors. The latest research progress on m6A methylation and radioresistance is reviewed in this article.

Abstract Background Circular RNA (circRNA) and N6‐methyladenosine (m6A) play a critical role in tumour occurrence and development, including colorectal cancer (CRC). However, little is known about the interaction between circRNA and m6A in the radiosensitivity of CRC. Here, we investigated the role of a novel m6A‐regulated circRNA in CRC. Methods Differentially expressed circRNAs from radiosensitive and radioresistant CRC tissues were screened. Modifications of the selected circRNAs were examined by methylated RNA immunoprecipitation assay. Finally, the selected circRNAs were subjected to radiosensitivity assay. Results We identified that circAFF2 is closely related to both radiosensitivity and m6A in CRC. CircAFF2 was highly expressed in patients with radiosensitive rectal cancer, and patients with high expression of circAFF2 had a better prognosis. In addition, circAFF2 can enhance the radiosensitivity of CRC cells both in vitro and in vivo. The regulation of circAFF2 involves ALKBH5‐mediated demethylation, followed by its recognition and degradation via YTHDF2. Rescue experiments revealed that circAFF2 could reverse the radiosensitivity induced by ALKBH5 or YTHDF2. Mechanistically, circAFF2 binds with CAND1, promotes the binding of CAND1 to Cullin1 and inhibits its neddylation, subsequently impacting the radiosensitivity of CRC. Conclusion We identified and characterised circAFF2 as a novel m6A‐modified circRNA and validated the ALKBH5/YTHDF2/circAFF2/Cullin‐NEDD8 axis as a potential radiotherapy target for CRC.

Radiotherapy, a treatment method employing radiation to eradicate tumor cells and subsequently reduce or eliminate tumor masses, is widely applied in the management of numerous patients with tumors. However, its therapeutic effectiveness is somewhat constrained by various drug-resistant factors. Recent studies have highlighted the ubiquitination/deubiquitination system, a reversible molecular modification pathway, for its dual role in influencing tumor behaviors. It can either promote or inhibit tumor progression, impacting tumor proliferation, migration, invasion, and associated therapeutic resistance. Consequently, delving into the potential mechanisms through which ubiquitination and deubiquitination systems modulate the response to radiotherapy in malignant tumors holds paramount significance in augmenting its efficacy. In this paper, we comprehensively examine the strides made in research and the pertinent mechanisms of ubiquitination and deubiquitination systems in governing radiotherapy resistance in tumors. This underscores the potential for developing diverse radiosensitizers targeting distinct mechanisms, with the aim of enhancing the effectiveness of radiotherapy.

Abstract Radiotherapy is among the routine treatment options for malignant tumors. And it damages DNA and other cellular organelles in target cells by using ionizing radiation produced by various rays, killing the cells. In recent years, multiple studies have demonstrated that exosomes are mechanistically involved in regulating tumor formation, development, invasion and metastasis, and immune evasion. The latest research shows that radiation can affect the abundance and composition of exosomes as well as cell-to-cell communication. In the environment, exosome-carried miRNAs, circRNA, mRNA, and proteins are differentially expressed in cancer cells, while these molecules play a role in numerous biological processes, including the regulation of oncogene expression, mediation of signaling pathways in cancer cells, remodeling of tumor-related fibroblasts, regulation of cell radiosensitivity, and so forth. Therefore, elucidation of the mechanism underlying the role of exosomes in radiotherapy of malignant tumors is crucial for improving the efficacy of radiotherapy. This review will summarize the research advances in radiosensitivity of malignant tumors related to exosomes.

Dynamic multileaf-collimator (DMLC) and volumetric modulation arc therapy (VMAT) were compared carefully in radiotherapy for esophagus cancer (EC) with the help of a new plan quality index: chair homogeneity index (CHI). Thirty-five patients with EC who underwent RT were enrolled. The prescription for the planning tumor volume (PTV) was 54Gy/25f and for the boost volume was 60Gy/25f. Two plans were designed for each patient: DMLC and VMAT. The dose-volume constraints were the same for two kinds of plans of each patient. CHI was an index developed by us and described the dose heterogeneity in the PTV but excluding the Boost (P–B). Heterogeneity index (HI), conformity index (CI) and other plan qualities indexes were also collected. The mean CHIs of PTV and P–B were 1.70 and 1.79 in DMLC, significantly higher than 0.82 and 0.86 in VMAT, respectively. The mean HIs of PTV and PTV-Boost were 17.79% and 15.55% in DMLC, slightly higher than 19.33% and 16.83% in VMAT, respectively. From the data aforementioned, DMLC is superior to VMAT in the treatment for EC. The high values of CHI in plans with DMLC proposed that DMLC achieve a more ideal dose distribution inside a compound target than VMAT.

Abstract RNA modification, like DNA methylation, histone modification, non-coding RNA modification and chromatin rearrangement, plays an important role in tumours. N6-methyladenosine (m6A) is the most abundant RNA modification in cells, and it regulates RNA transcription, processing, splicing, degradation, and translation. m6A-associated proteins have been used as new biomarkers and therapeutic targets for tumour prediction and monitoring. There are three main types of proteins involved in m6A methylation: methyltransferases (METTL3, METTL14, WTAP, RBM15, ZC3H13 and KIAA1429), demethylases (FTO, ALKBH5 and ALKBH3) and RNA-binding proteins (YTHDF1-3, YTHDC1-2, IGF2BPs and HNRNPs). This article reviews the origins, characteristics and functions of m6A and its relationship with digestive system tumours based on recent research. The expression of m6A regulators can be used as an evaluation indicator of tumour growth and progression and as a prognostic indicator. In-depth research on m6A methylation in digestive system tumours may provide new directions for clinical prediction and further treatment.

Abstract Background CircRNAs play crucial roles in multiple tumours. However, the functions of most circRNAs in cervical cancer remain unclear. Methods This study collected GSE113696 data from the GEO database to search for differentially expressed circRNAs in cervical cancer. Quantitative reverse transcription PCR was used to detect the expression level of circNEIL3 in cervical cancer cells and tissues. Then, functional experiments in vitro and in vivo were performed to evaluate the effects of circNEIL3 in cervical cancer. Results CircNEIL3 was highly expressed in cervical cancer. In vivo and in vitro experiments verified that circNEIL3 enhanced the proliferation capacity of cervical cancer cells. RNA immunoprecipitation, luciferase reporter assay, pull-down assay, and fluorescent in situ hybridization confirmed the interaction between circNEIL3 and miR-137 in cervical cancer. A luciferase reporter assay showed that circNEIL3 adsorbed miR-137 and upregulated KLF12 to regulate the proliferation of cervical cancer cells. Conclusions CircNEIL3 is an oncogene in cervical cancer and might serve as a ceRNA that competitively binds to miR-137, thereby indirectly upregulating the expression of KLF12 and promoting the proliferation of cervical cancer cells.

Abstract Background Patients with regional lymph node recurrence after radical resection of esophageal cancer have poor therapeutic outcomes. Currently, there is no standard treatment for regional lymph node recurrence, and its prognostic risk factors are not well-understood. This study retrospectively analyzed 83 patients with postoperative regional lymph node recurrence after radical resection of esophageal squamous cell carcinoma. The aim was to evaluate the clinical efficacy and prognostic factors of salvage radiotherapy with or without chemotherapy in these patients. Methods The survival and prognostic factors of 83 patients with esophageal squamous cell carcinoma with regional lymph node recurrence after radical surgery were retrospectively analyzed. All patients underwent radiotherapy, of which 74 patients received volumetric modulated arc therapy (VMAT), 9 patients received three-dimensional conformal radiation therapy (3DCRT), administered using a conventional segmentation protocol with a dose distribution range of 50.4–66.2Gy (median dose of 60Gy). In total, 41 patients received radiotherapy alone, 42 received radiotherapy combined with chemotherapy, and the concurrent chemotherapy regimen was mainly composed of either platinum or fluorouracil monotherapy, except for 4 patients who were given 5-fluorouracil plus platinum (FP) or paclitaxel plus platinum (TP). Results The median follow-up time was 24 (range, 9–75) months. The overall survival (OS) rates at 1 year, 2 years, 3 years, and 5 years were 83.0, 57.1, 40.1, and 35.1%, respectively. The median overall survival (OS) time was 18 (range, 5–75) months. The 3-year survival rate was 47.5% in patients with radiation alone and 41.9% in patients receiving concurrent chemoradiotherapy(p = 0.570), while the response rate (CR + PR) in those two groups was 73.2 and 91.4%, respectively. By multivariate analysis of OS, age (worse in younger patients, p = 0.034) was found to be significantly associated with disease prognosis. The commonly toxicities were esophagitis, neutropenia and anemia. 18% patients experienced grade 3 toxicity and no treatment-related death occurred. Conclusions These results of this retrospective analysis suggest that radiotherapy with or without chemotherapy is an effective and feasible salvage treatment for lymph node recurrence after radical resection of esophageal squamous cell carcinoma.

Abstract Breast-conserving surgery (BCS) plus postoperative radiotherapy has become the standard treatment for early-stage breast cancer. The aim of this study was to compare the setup accuracy of optical surface imaging by the Sentinel system with cone-beam computerized tomography (CBCT) imaging currently used in our clinic for patients received BCS. Two optical surface scans were acquired before and immediately after couch movement correction. The correlation between the setup errors as determined by the initial optical surface scan and CBCT was analyzed. The deviation of the second optical surface scan from the reference planning CT was considered an estimate for the residual errors for the new method for patient setup correction. The consequences in terms for necessary planning target volume (PTV) margins for treatment sessions without setup correction applied. We analyzed 145 scans in 27 patients treated for early stage breast cancer. The setup errors of skin marker based patient alignment by optical surface scan and CBCT were correlated, and the residual setup errors as determined by the optical surface scan after couch movement correction were reduced. Optical surface imaging provides a convenient method for improving the setup accuracy for breast cancer patient without unnecessary imaging dose.

Background: In the present study, we aimed to investigate the role of epidermal growth factor receptor (EGFR) pathway in the up-regulation of programmed death ligand-1 (PD-L1) caused by radiotherapy (RT). Materials and Methods: Tissue microarrays (TMA) consisting of glioma cancer specimens from 64 patients were used to examine the correlation between PD-L1 and EGFR levels. Furthermore, we performed in vitro experiments to assess the role of EGFR pathway in RT-upregulated PD-L1 expression using human glioma cell lines U87 and U251. Results: Our data demonstrated that the PD-L1 expression was significantly correlated with EGFR expression in glioma specimens (χ2 = 5.00, P = 0.025). The expressions of PD-L1 at the protein and mRNA levels were both significantly up-regulated by RT (P 0.05). The combination of RT with EGFR inhibitor exhibited the same effect on antitumor immune response compared with the combination of RT with PD-L1 neutralizing antibody (Ab). Conclusions: RT could up-regulate the PD-L1 expression through the pathways downstream of EGFR in glioma.

Abstract The aim of this study was to investigate the impact of local treatment modalities on the survival of patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB-IIB cervical cancer, including cancer-directed surgery (CDS) alone and CDS combined with radiotherapy (RT). A total of 8,357 patients with cervical cancer between 1988 and 2013 were included in the final study cohort, including 4,298 (51.4%) patients who underwent CDS alone and 4,059 (48.6%) patients who received combination therapy. Univariate and multivariate analyses showed that local treatment modalities were prognostic factors for cause-specific survival (CSS). Patients who received combination therapy had worse CSS (HR = 1.38; 95% CI = 1.20–1.59; P

Abstract Irradiation on hippocampus would lead to neuro-cognitive dysfunction in locally advanced nasopharyneal carcinoma (LA-NPC) patients accepting radiotherapy. Our study here aimed to investigate if undergoing hippocampus sparing (HS) volume modulated arc therapy (VMAT) would influence the plan quality in LA NPC patients. We designed three kinds of radiotherapeutic plans for 11 LA NPC patients: conventional VMAT (C-VMAT), HS-VMAT and HS intensity modulated radiation therapy with dynamic multileaf collimator (HS-dMLC). And the dose distribution on targets and surrounding organs at risk (OAR) were carefully evaluated. We found out that the expected doses on hippocampus were significantly lowered in HS-VMAT (899 ± 378 cGy) and HS-dMLC (896 ± 321 cGy) as compared to C-VMAT (1518 ± 337 cGy, p 0.05). Moreover, lower radiation doses on brain stem were observed in HS-VMAT plan in comparison with C-VMAT plan (p

Background: It has been reported that miR-203 expression was aberrant in various types of cancers, and it could be used as a prognostic biomarker. Therefore, in this study, we aimed to evaluate the prognostic value of miR-203 expression in solid tumors by using meta-analysis and The Cancer Genome Atlas (TCGA) datasets. Methods: By doing a literature research in PubMed, Embase and the Cochrane Library (last update by December 2016), we were able to identify the studies assessing the prognostic role of miR-203 in various tumors. We then used TCGA datasets to validate the results of meta-analysis. Results:33 studies from 26 articles were qualified and enrolled in this meta-analysis. Pooled analyses showed that higher expression of miR-203 in tissues couldn’t predict poor overall survival (OS) and progression-free survival (PFS) in solid tumors. However, the results of subgroup analyses revealed that the upregulation of tissue miR-203 expression was associated with poor OS in colorectal cancer (hazard ratio (HR)=1.81, 95% confidence intervals (CI) 1.31-2.49; P

Background: Recently, many studies have shown that microRNAs (miRNA) exhibit altered expression in various cancers and may serve as prognostic biomarkers. We performed a systematic review and meta-analysis to evaluate the prognostic role of miR-200c expression in different cancers. Methods: Studies were recruited by searching PubMed, Embase and the Cochrane Library (last search update was May 2014) and assessed by further quality evaluation. Results: A total of 25 studies dealing with various carcinomas were identified for systematic review. Among them, 18 studies were ultimately included in the meta-analysis. Our results indicated that the expression of tissue miR-200c was not associated with OS and PFS in various carcinomas; however, downregulation of tissue miR-200c did predict poor OS of patients with stage I disease (HR=0.41, 95% CI 0.25-0.68, P=0.001). Furthermore, overexpression of blood miR-200c was significantly related to poor OS and PFS (HR=3.07 95% CI 1.58-5.96 P=0.001, HR=2.26 95% CI 1.66-3.08 PConclusion: This systematic review and meta-analysis clarified that low expression of miR-200c in primary tissue was significantly associated with poor survival in cancer patients at early stage, whereas a high level of blood miR-200c predicted poor prognosis in patients with advanced tumors.

Abstract Autophagy is a dynamic self-renovation biological process that maintains cell homeostasis and is responsible for the quality control of proteins, organelles, and energy metabolism. The E1-like ubiquitin-activating enzyme autophagy-related gene 7 (ATG7) is a critical factor that initiates classic autophagy reactions by promoting the formation and extension of autophagosome membranes. Recent studies have identified the key functions of ATG7 in regulating the cell cycle, apoptosis, and metabolism associated with the occurrence and development of multiple diseases. This review summarizes how ATG7 is precisely programmed by genetic, transcriptional, and epigenetic modifications in cells and the relationship between ATG7 and aging-related diseases.

Fruit wart is an important appearance trait influencing consumer preferences of bitter gourd (Momordica charantia L.). The molecular genetic mechanisms underlying fruit wart formation in bitter gourd are largely unknown. In this study, genetic analysis based on four generations showed that fruit wart formation in bitter gourd was controlled by a single dominant locus named as Fwa. The Fwa locus was initially mapped into a 4.82 Mb region on pseudochromosome 4 by BSA-seq analysis and subsequently narrowed down to a 286.30 kb region by linkage analysis. A large F2 population consisting of 2 360 individuals was used to screen recombinants, and the Fwa locus was finally fine mapped into a 22.70 kb region harboring four protein-coding genes through recombination analysis. MC04g1399, encoding an epidermal patterning factor 2-like protein, was proposed as the best candidate gene for Fwa via sequence variation and expression analysis. In addition, a 1-bp insertion and deletion (InDel) variation within MC04g1399 was converted to a cleaved amplified polymorphic sequence (CAPS) marker that could precisely distinguish between the warty and non-warty types with an accuracy rate of 100% among a wide panel of 126 bitter gourd germplasm resources. Our results not only provide a scientific basis for deciphering the molecular mechanisms underlying fruit wart formation but also provide a powerful tool for efficient genetic improvement of fruit wart via marker-assisted selection.

Abstract We report that autophagy-related gene 7 (ATG7) modulates p53 activity to regulate cell cycle and survival during metabolic stress, and that indicates Atg7 is functionally involved in cellular homeostasis in autophagy independent fashion. As a protein translation inhibitor, Programmed cell death 4 (PDCD4) expression is regulated by AKT1 phosphorylation. Here, we find that Atg7 interacts with PDCD4 and AKT1 to regulate AKT1-PDCD4 phosphorylation-ubiquitination axis during metabolic stress. We demonstrate that Atg7 senses decrease of ATP levels to suppress AKT-mediated PDCD4 phosphorylation at Ser67, which inhibits PDCD4 ubiquitinating during metabolic stress. Finally, PDCD4 accumulates and functions as a protein translation inhibitor to conserve energy, thus reducing apoptosis and allowing cells to survive stress periods. These results suggest that the ATP-Atg7-PDCD4 axis acts as a metabolic adaptation pathway which dictates cells to overcome metabolic stress.

Reactive oxygen species (ROS) play a pivotal role in macrophage-mediated acute inflammation. However, the precise molecular mechanism by which ROS regulate macrophage polarization remains unclear. Here, we show that ROS function as signaling molecules that regulate M1 macrophage polarization through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (Chk2), vital effector kinases in the DNA damage response (DDR) signaling pathway. We further demonstrate that Chk2 phosphorylates PKM2 at the T95 and T195 sites, promoting glycolysis and facilitating macrophage M1 polarization. In addition, Chk2 activation increases the Chk2-dependent expression of p21, inducing cell cycle arrest for subsequent macrophage M1 polarization. Finally, Chk2-deficient mice infected with lipopolysaccharides (LPS) display a significant decrease in lung inflammation and M1 macrophage counts. Taken together, these results suggest that inhibiting the ROS-Chk2 axis can prevent the excessive inflammatory activation of macrophages, and this pathway can be targeted to develop a novel therapy for inflammation-associated diseases and expand our understanding of the pathophysiological functions of DDR in innate immunity.