Xishan Yang, Qitai Chen, YuJie Yu, Yi Zang, Rujia Zheng, Zhe Zhang, Shuaijun Lu, Li Zhou
{"title":"Oxidative Stress and DNA Epigenetic Modifications in Cancer: Mechanisms and Targeted Therapeutics","authors":"Xishan Yang, Qitai Chen, YuJie Yu, Yi Zang, Rujia Zheng, Zhe Zhang, Shuaijun Lu, Li Zhou","doi":"10.1002/mog2.70065","DOIUrl":"10.1002/mog2.70065","url":null,"abstract":"<p>Oxidative stress, defined as an imbalance between the production and clearance of reactive oxygen species (ROS), is not merely a reflection of metabolic or microenvironmental stress but an active signaling and regulatory hub in cancer. ROS function as key signaling molecules that drive tumorigenesis, metabolic reprogramming, and epigenetic remodeling. However, a systematic view of the spatiotemporally organized, bidirectional crosstalk between ROS and the DNA epigenetic machinery, particularly under conditions such as hypoxia, remains incomplete. This review synthesizes current understanding of this bidirectional axis. We detail how ROS reshape the DNA epigenetic landscape by modulating DNA methyltransferases and ten-eleven translocation family protein (TET) dioxygenases, altering profiles of 5-methylcytosine and its oxidized derivatives, and how epigenetic modifications in turn regulate ROS homeostasis through antioxidant and metabolic pathways. We further explore the cascade regulation of this interaction within the hypoxic tumor microenvironment and evaluate combined intervention strategies targeting both redox and epigenetic mechanisms. Emerging therapeutic avenues are highlighted, including spatiotemporally controlled ROS modulation, CRISPR-based epigenome editing, ROS-responsive proteolysis-targeting chimeras, artificial intelligence (AI)-driven multi-omics prediction, and tissue-specific delivery platforms. By integrating these insights, this review provides a framework for developing ROS-guided precision epigenetic reprogramming strategies, offering novel therapeutic opportunities in cancer.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"5 2","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147668424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"X-Linked Inhibitor of Apoptosis Protein (XIAP) Contributes to ERK1/2-Mediated Anoikis Resistance in Hepatocellular Carcinoma","authors":"Qingyu Zeng, Zun Mao, Sumin Sun, Zhixiang Gao, Junpeng Mu, Zhaoji Pan, Qing Li, Xueyuan Mao, Jianbo Xu, Dousheng Bai, Shile Huang, Long Chen","doi":"10.1002/mog2.70059","DOIUrl":"10.1002/mog2.70059","url":null,"abstract":"<p>X-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein that regulates many cellular functions. Anoikis resistance is necessary for hepatocellular carcinoma (HCC) intrahepatic spread and extrahepatic metastasis. However, limited information is available regarding the mechanism of XIAP underlying the resistance of HCC cells to anoikis. Here we show an increased expression of XIAP in microvascular tumor thrombosis (MVTT) of HCC, which is positively correlated with the expression of extracellular signal-regulated kinases 1/2 (ERK1/2). HCC cells exhibit an increase in XIAP expression when detached, leading to their resistance to anoikis. Furthermore, enhanced phosphorylation of XIAP promotes resistance to anoikis in HCC cells. In addition, the zinc-binding baculovirus IAP repeat (BIR) domains of XIAP, instead of the highly intriguing novel gene (RING) domain, are responsible for conferring resistance to anoikis in HCC cells. Importantly, our findings indicate that ERK1/2 can control the expression of XIAP, leading to the resistance of HCC to anoikis in cell-based and mouse models. The significance of the interaction between XIAP and ERK1/2 in resisting anoikis is emphasized by our discoveries, presenting novel avenues for HCC treatment.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"5 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147579894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The JAK/STAT Pathway in Cancer: From Molecular Mechanisms to Clinical Applications","authors":"Yixing Liao, Qi Wei, Hongjun Song, Hao Zeng, Chang Qi, Yunchang Meng, Yuanyuan Zhang, Yuanyuan Zhang, Weimin Li, Yalun Li, Panwen Tian","doi":"10.1002/mog2.70063","DOIUrl":"10.1002/mog2.70063","url":null,"abstract":"<p>The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a critical communication hub that translates extracellular signals into gene expression programs. Its aberrant activation serves as a central driver of tumorigenesis, metastasis, and immunosuppression in diverse malignancies. With research expanding from hematologic malignancies to solid tumors, the JAK/STAT pathway has gradually emerged as a promising therapeutic target for cancer treatment. This review systematically analyzes the multi-dimensional dysregulation of the JAK/STAT pathway, encompassing somatic mutations, epigenetic modifications, and aberrant cytokine networks. We elucidate critical non-canonical functions that underpin metabolic reprogramming and chromatin stability. Furthermore, we detail the pathway's pivotal role in bridging tumor cells with the microenvironment, focusing on myeloid-derived suppressor cells (MDSC) recruitment and the reciprocal STAT3/PD-L1 axis that fuels immune evasion and therapeutic resistance. Finally, we comprehensively evaluate the shifting therapeutic landscape, advocating for a transition from broad-spectrum kinase inhibitors to high-precision modalities such as allosteric modulators, proteolysis targeting chimeras (PROTACs), and novel combination strategies. By integrating the advance in the JAK/STAT pathway with cancer, this review underscores the potential of targeting this signaling axis for cancer therapy.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"5 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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