BackgroundSustained TGF-β1 secretion is a key driver of radiation-induced inflammation and fibrosis (RIF), but the underlying mechanisms remain incompletely defined. This study investigated whether radiation-induced mitochondrial dysfunction activates cytosolic mitochondrial DNA (mtDNA) sensing via the cGAS-STING-NF-κB axis to perpetuate TGF-β1 release, and evaluated the therapeutic potential of Captopril.MethodsHuman endothelial cells (EA.hy926) received fractionated X-ray irradiation (total 40 Gy/20 fractions) to establish a long-term radiation model (EA-R). Mitochondrial integrity, cytosolic mtDNA release, and pathway activation were assessed using siRNA and inhibitors. Clinical relevance was evaluated in normal tissue specimens from 119 rectal cancer patients (68 with radiotherapy vs. 51 without) and a prospective randomized trial of 204 abdominal cancer patients (Captopril, n=100; Control, n=104).ResultsFractionated irradiation induced persistent mitochondrial dysfunction in EA-R cells, characterized by reduced complex I activity, decreased membrane potential, and disrupted cristae architecture. This damage triggered TDP-43 translocation to mitochondria, leading to sustained, membrane potential-dependent mtDNA release into the cytoplasm. Cytosolic mtDNA activated the cGAS-STING-NF-κB pathway, resulting in continuously elevated TGF-β1 secretion for over one year post-irradiation. Knockdown of cGAS or STING, or NF-κB inhibition, significantly attenuated TGF-β1 production. Overexpression of NDUFS1 restored mitochondrial function and suppressed the cascade. In clinical specimens, irradiated rectal tissues showed significantly higher expression of TDP-43, STING, and TGF-β1 (P < 0.0001). In the prospective trial, Captopril significantly lowered serum TGF-β1 levels at one month post-radiotherapy (P < 0.01) and reduced acute toxicities, including hematological toxicity (P = 0.001), elevated transaminase (P = 0.018), and elevated bilirubin (P = 0.034).ConclusionsRadiation triggers TDP-43-dependent mtDNA release via mitochondrial dysfunction, activating the cGAS-STING-NF-κB axis to sustain TGF-β1 production. Captopril suppresses this pathway, reduces TGF-β1, and mitigates acute radiation toxicities, identifying mitochondrial retrograde signaling as a potential therapeutic target for preventing RIF.

The stiffness of the matrix is closely related to the progression of hepatocellular carcinoma (HCC). Although direct targeting of stromal rigidity in HCC remains a clinical challenge, cancer-associated fibroblasts (CAFs) are considered key contributors to this process. Given the heterogeneity of CAFs, this study explored the relationship between specific CAF subsets and liver cancer matrix stiffness, aiming to identify novel therapeutic targets for HCC patients. Single-cell sequencing datasets were leveraged to identify cell types within liver cancer and characterize the transcriptomic profiles of CAFs. Prognostic analysis, utilizing the Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) liver cancer datasets, assessed the correlation between matrix stiffness-related genes and HCC patient outcomes. Pseudo-time analysis was applied to trace the developmental trajectories of CAFs. By calculating intercellular communication probabilities and analyzing transcription factor activity, the functions and interactions of different CAF subsets were elucidated. Gene Ontology (GO) analysis was used to explore the functional roles of CAFs in distinct Yes-associated protein 1 (YAP1) groups. Finally, cellular experiments and animal experiments were further conducted to validate the hypotheses of this study. This study identified CAF subpopulations based on single-cell sequencing data and analyzed transcriptional changes within these subpopulations. Key findings include the identification of collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and lysyloxidase (LOX) as pivotal node genes during CAF development. Moreover, the expression of matrix stiffness-related genes was inversely correlated with the prognosis of HCC patients. Notably, the YAP1-positive CAF subpopulation emerged as the primary contributor to matrix stiffness in liver cancer. This subpopulation upregulates the expression of matrix stiffness-related genes and promotes tumor progression by activating signaling pathways such as autophagy and GTPase activity regulation. Cellular experiments and animal studies further validated this conclusion. This single-cell analysis uncovered the functional roles of CAFs in liver cancer. The YAP1-positive CAF subpopulation, in particular, was shown to contribute to matrix stiffness by upregulating the expression of relevant genes and promoting tumor progression through the activation of specific signaling pathways.

Radiation resistance is the leading cause of radiotherapy failure in patients with cancer. Enhanced DNA damage repair is the main reason for cancer cells to develop resistance to radiation. Autophagy has been widely reported to be linked to increased genome stability and radiation resistance. Mitochondria are highly involved in the cell response to radiotherapy. However, the autophagy subtype mitophagy has not been studied in terms of genome stability. We have previously demonstrated that mitochondrial dysfunction is the cause of radiation resistance in tumour cells. In the present study, we found that SIRT3 was highly expressed in colorectal cancer cells with mitochondrial dysfunction, leading to PINK1/Parkin‐mediated mitophagy. Excessive activation of mitophagy enhanced DNA damage repair, therefore promoting the resistance of tumour cells to radiation. Mechanistically, mitophagy resulted in decreased RING1b expression, which led to a reduction in the ubiquitination of histone H2A at K119, thereby enhancing the repair of DNA damage caused by radiation. Additionally, high expression of SIRT3 was related to a poor tumour regression grade in rectal cancer patients treated with neoadjuvant radiotherapy. These findings suggest that restoring mitochondrial function could be an effective method for increasing the radiosensitivity of patients with colorectal cancer.

Ferroptosis, featuring an iron‐dependent peroxidation of lipids, is a novel form of programmed cell death that may hold great potential in cancer therapy. Our study found that palmitic acid (PA) inhibited colon cancer cell viability in vitro and in vivo , in conjunction with an accumulation of reactive oxygen species and lipid peroxidation. The ferroptosis inhibitor Ferrostatin‐1 but not Z‐VAD‐FMK (a pan‐caspase inhibitor), Necrostatin‐1 (a potent necroptosis inhibitor), or CQ (a potent inhibitor of autophagy), rescued the cell death phenotype induced by PA. Subsequently, we verified that PA induces ferroptotic cell death through excess iron as cell death was inhibited by iron chelator deferiprone (DFP), while it was exacerbated by a supplement of ferric ammonium citrate. Mechanistically, PA affects intracellular iron content by inducing endoplasmic reticulum (ER) stress leading to ER calcium release and regulating transferrin (TF) transport through increasing cytosolic calcium levels. Furthermore, we observed that cells with high expression of CD36 were more vulnerable to PA‐induced ferroptosis. Altogether, our findings reveal that PA engages in anti‐cancer properties by activating ER stress/ER calcium release/TF‐dependent ferroptosis, and PA might serve as a compound to activate ferroptosis in colon cancer cells with high CD36 expression.

Introduction: Aberrations in cell cycle control is defined as one of the hallmarks of cancer, while cyclin D1 is an essential protein to cell cycle which promote G1 phase into S phase, and frequently overexpressed in many human cancers. However, new functions have been identified in transgenic mice models, including the transcription of genome, the development of chromosome instability and DNA repair. In this research, our aim is to find the function of cyclin D1 in transcription in human cancers. Methods: The correlation of the cyclin D1 expression levels and prognosis of cervical cancer patients were analyzed in tissue microarray (TMA) cohort. We chose C33A as our main research object. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq), to find out the genes differentially expressed in C33A, cyclin D1 knock-in C33A and cyclin D1 knock-down C33A. Results: We found that upregulation of cyclin D1 was associated with shorter overall survival (OS) and disease-free survival (DFS). Functionally, we identified 422 genes differentially expressed through analysis of the results of ChIP-seq and RNA-seq. These genes are highly enriched in Gene Ontology categories and involve in diverse cellular functions via KEGG classification, including replication and repair, signal transduction, cell growth and death. Conclusion: These findings suggested that the expression of cyclin D1 was associated with the prognosis of patients with cervical cancer. Cyclin D1 can serve both to activate and downregulate gene expression as a transcriptional role directly binding with genome DNA, which means that cyclin D1 may be a key protein during oncogenesis and tumor development.

Objective:To investigate epithelial-mesenchymal transition and to explore the effects of mitochondrial dysfunction and increased expression of TGF-β1 pathway on epithelial-mesenchymal transition (EMT) in pancreatic adenocarcinoma after X-ray irradiation.Methods:Split-dose irradiations of total 40 Gy (2 Gy × 20 and 4 Gy × 10) of 6 MV X-rays were performed on PATU1 988 t cells. The migration of the cells were examined through transwell filter chambers. Real-time PCR was adopted to detect the expression of EMT-related factors E-cadherin, Vimentin, N-cadherin, and MMPs (MMP2 and MMP9), critical subunits of mitochondrial complex I, and TGF-β1. The expression of EMT-related factors and content of TGF-β1 was detected after carbonylcyanide-m-chlorophenylhydrazone(CCCP) treatment. Meanwhile, the migration potential of pancreatic cells was detected after small interfering RNA (siRNA) knockdown of the expression of TGF-β1.Results:After irradiation, the migration capacities of the cancer cells increased ( t=21.90, 35.64, P<0.05). The expression of N-cadherin ( t=4.42, 4.77, P<0.05), Vimentin ( t=4.57, 3.02, P<0.05), MMP2 ( t=7.27, 26.08, P<0.05), and MMP9 ( t=13.26, 7.29, P<0.05) all increased, while the expression of E-cadherin deceased ( t=8.37, 6.77, P<0.05). The expression of TGF-β1 ( t=90.49, 35.17, P<0.05) increased. The expression of TGF-β1 decreased with small interfering RNA, which paralleled the inhibition of the epithelial-mesenchymal transition and migration ( t=38.66, 11.54, P<0.05). Mitochondrial dysfunction was reflected by the decline in the membrane potential ( t=6.94, 29.71, P<0.05) and complex-related subunits. The expression of TGF-β1 ( t=47.93, P<0.05) and EMT-related factors further increased after mitochondrial function was destroyed ( t=16.51, P<0.05). Conclusions:Radiation-induced mitochondrial dysfunction can increase the expression of TGF-β1, which promotes epithelial-mesenchymal transition, and result in the migration of pancreatic cancer cell line.

Mitochondrial retrograde signaling (mito-RTG) triggered by mitochondrial dysfunction plays a potential role in regulating tumor metabolic reprogramming and cellular sensitivity to radiation. Our previous studies showed phos-pyruvate dehydrogenase (p-PDH) and PDK1, which involved in aerobic glycolysis, were positively correlated with radioresistance, but how they initiate and work in the mito-RTG pathway is still unknown. Our further genomics analysis revealed that complex I components were widely downregulated in mitochondrial dysfunction model. In the present study, high expression of p-PDH was found in the complex I deficient cells and induced radioresistance. Mechanistically, complex I defects led to a decreased PDH both in cytoplasm and nucleus through [Ca2+]m-PDP1-PDH axis, and decreased PDH in nucleus promote DNA damage repair (DDR) response via reducing histone acetylation. Meanwhile, NDUFS1 (an important component of the complex I) overexpression could enhance the complex I activity, reverse glycolysis and resensitize cancer cells to radiation in vivo and in vitro. Furthermore, low NDUFS1 and PDH expression were validated to be correlated with poor tumor regression grading (TRG) in local advanced colorectal cancer (CRC) patients underwent neoadjuvant radiotherapy. Here, we propose that the [Ca2+]m-PDP1-PDH-histone acetylation retrograde signaling activated by mitochondrial complex I defects contribute to cancer cell radioresistance, which provides new insight in the understanding of the mito-RTG. For the first time, we reveal that NDUFS1 could be served as a promising predictor of radiosensitivity and modification of complex I function may improve clinical benefits of radiotherapy in CRC.

Viral infection activates the cGAS-STING signaling pathway and induces an antiviral response with in-creased expression of a series of cytokines including interferon. If the antiviral effect fails to effectively inhibit virus replication and eliminate the virus, normal alveolar tissue will be destroyed by the virus and serious inflammatory reaction. The primary autopsy confirmed the destruction of bronchoalveolar epithe-lial cells and interstitial tissues and server inflammatory injury. In the absence of effective antiviral drugs, it is important that the antiviral immunity and anti-oxidant stress are the main measures to prevent the progress of the disease. Aspirin plays an important role in blocking the pathway of cGAS-STING-cytokines. High dose vitamin C can alleviate the oxidative injury and promote tissue repair, therefor to reduce the mortality of 2019 novel coronavirus pneumonia and shorten the days staying in ICU. Early clinical interven-tion of aspirin and high dose vitamin C is recommended.

病例1,孕妇26岁,孕23周,孕1产0.超声发现胎儿下腹壁宽2.05 cm回声连续性中断,下腹部至会阴部见3.86 cm×2.75 cm包块向外突起(图1A),内见肠管、肝脏、胆囊回声,膀胱未显示;右侧脐动脉可显示,左侧脐动脉未显示;左足姿势异常,呈马蹄内翻状;脊柱骶尾段表面皮肤完整,骶尾段椎体横切面呈“V”字形,并见1.08 cm×0.91 cm无回声包块稍向外突起,骶尾段椎体骨化中心显示欠清晰;外生殖器显示不清.