Unveiling the vital role of OGG1 in inflammation, vascular endothelial damage, and cell death in obstetric and gynecological diseases

OGG1 has been implicated in the pathophysiology of several obstetric and gynecological diseases, including polycystic ovary syndrome, endometriosis, preeclampsia, preterm birth, and gynecologic cancers. In these conditions, oxidative stress and inflammation are central pathological features, with OGG1 contributing to cellular processes such as DNA repair, apoptosis, and regulation of inflammatory responses. The involvement of OGG1 in these diseases suggests its potential as both a biomarker and a therapeutic target, although further research is required to fully elucidate its role in these pathologies. Polycystic ovary syndrome is the most common reproductive endocrine disorder among women, characterized by a complex pathophysiology and a wide range of clinical manifestations. Oxidative stress and chronic low-grade inflammation are key pathogenic processes involved in polycystic ovary syndrome, significantly affecting ovarian function and contributing to metabolic abnormalities [ 92 , 93 ]. Several studies have reported significantly elevated levels of pro-inflammatory cytokines (e.g., IFN-γ, IL-2, TNF-α, IL-6, and IL-23) within the follicular fluid of patients with polycystic ovary syndrome [ 94 , 95 ]. Furthermore, Xia et al. reported significantly elevated OGG1 protein expression in granulosa cells from PCOS patients, and also measured higher OGG1-related signal levels in serum and follicular fluid using ELISA, although the precise extracellular form and functional relevance of OGG1 in these fluids remains to be clarified [ 96 ]. Increased apoptosis in granulosa cells is a key pathogenic feature of ovaries affected by pathological ovary syndrome. This increase can impair follicular development, reduce oocyte quality, and affect the success rates of in vitro fertilization–embryo transfer (IVF-ET) procedures [ 97 ]. The administration of TH5487, a functional inhibitor of OGG1, leads to increased apoptosis and ROS production in ovarian granulosa cells, accompanied by a reduction in their inflammatory responses. These findings suggest that OGG1 may contribute to the pathogenesis of polycystic ovary syndrome by promoting activation of the NF-κB pathway and increasing IL-6 secretion [ 96 ]. This evidence further supports the anti-apoptotic and pro-inflammatory roles of OGG1 in the pathogenesis of polycystic ovary syndrome. However, the precise role of OGG1 in Polycystic ovary syndrome remains to be fully elucidated. Endometriosis is a reproductive disorder in women characterized by the ectopic growth of endometrial cells and tissues outside the uterus. It is associated with ectopic endometrial tissue, immune system alterations, imbalances in cell growth and death, abnormal hormone signaling, and genetic factors [ 98 , 99 ]. Carvalho et al. reported significantly increased levels of lipid peroxides and protein carbonyls in the peritoneal fluid of patients with endometriosis. Additionally, immunohistochemical analysis revealed elevated 8-OHdG levels, whereas OGG1 expression was significantly reduced, indicating impaired oxidative DNA repair capacity [ 100 ]. These findings suggest that oxidative cell damage is a significant factor underlying the progression of endometriosis. NF-κB promotes the growth and persistence of endometriotic cells by regulating angiogenesis, invasion, proliferation, and inflammation, thereby contributing to the progression of endometriosis [ 101 ]. An imbalance between estrogen, which promotes endometrial growth, and progesterone, which counteracts its effects and promotes differentiation, leads to impaired uterine function, immune cell infiltration, and inflammation. Additionally, aberrant angiogenesis and impaired apoptosis are key pathophysiological factors driving the progression of this condition [ 102 ]. A study by Siracusa et al., using a rat model of endometriosis induced by uterine debris injection, demonstrated that rapamycin-triggered autophagy and mitophagy result in enhanced apoptosis and reduced angiogenesis, leading to smaller lesion volumes, areas, and diameters [ 103 ]. Given the involvement of NF-κB, dysregulated angiogenesis, apoptosis, and autophagy in the pathophysiology of endometriosis, it can be inferred that OGG1 may promote inflammation and autophagy while inhibiting angiogenesis. However, this hypothesis requires further experimental validation. Preeclampsia is a progressive multisystem disorder of pregnancy and a leading cause of maternal and fetal morbidity and mortality. Although the etiology and pathogenesis of preeclampsia are not fully understood, they are thought to involve maternal, placental, and fetal factors, including abnormalities in uteroplacental vascular development, dysregulated maternal immune responses, and the altered secretion of pro-inflammatory, angiogenic, and anti-angiogenic mediators [ 104 ]. Oxidative stress at the maternal–fetal interface, which normally supports placental development by regulating oxidative balance and apoptosis, becomes dysregulated in preeclampsia, contributing to pathological outcomes [ 105 ]. In pathological pregnancy conditions, such as preeclampsia, the levels of 8-oxoG are elevated [ 106 – 108 ]. Scaife et al. demonstrated that placental senescence markers—such as p21, phosphorylated histone γH2AX, and 8-oxoG—increase with gestational age. These markers are also significantly elevated in pathological and post-term placentas, suggesting that oxidative stress-induced senescence plays a pivotal role in the progression of preeclampsia [ 109 ]. An abnormal maternal immune response to the placenta is a key step in the pathogenesis of preeclampsia, triggering a systemic inflammatory response that impacts endothelial function [ 110 ]. Immune cells, such as Th1, Th17, and natural killer (NK) cells, play critical roles in the pathogenesis of preeclampsia. In patients with preeclampsia, increased proportions of pro-inflammatory T cell subsets (Th1 and Th17), along with decreased levels of immunosuppressive populations (Tregs and Th2), have been observed [ 111 , 112 ]. Furthermore, diminished Treg levels in early pregnancy have been associated with an increased risk of preeclampsia progression [ 51 , 113 ]. Research conducted by Tadesse et al. indicated that placental tissues from patients with preeclampsia exhibit markedly high levels of OGG1 and APE1. Moreover, in placental tissues affected by oxidative stress, the expression of OGG1 and APE1 in maternal cells (decidua) significantly exceeds that in fetal cells (cytotrophoblasts) [ 114 ]. However, the precise role of OGG1 and its downstream products in endothelial oxidative injury and immune activation in eclampsia remains to be elucidated. In addition to being closely associated with various reproductive disorders, oxidative stress is also linked to pregnancy complications, such as preterm birth [ 108 ]. In this condition, the inflammatory response at the placental–maternal interface is a crucial factor. The combined effects of inflammatory responses and oxidative stress at the placental–maternal interface contribute to the transformation and senescence of membrane cells. This process, in turn, leads to the release of pro-inflammatory and pro-contractile mediators, ultimately triggering the onset of both term and preterm labor [ 115 ]. Menon et al. reported that human placental membranes express OGG1, and that exposure to cigarette smoke induces DNA damage accumulation and elevates basal 8-oxoG levels in these tissues. This highlights the critical role of OGG1 in preserving genomic integrity and preventing preterm birth and premature rupture of fetal membranes [ 116 ]. However, current literature on the role of OGG1 in pregnancy complications remains limited and warrants further investigation. The altered hydrogen-bond donor and acceptor configuration of 8-oxoG, particularly involving protonation of the N7 position, converts it from a hydrogen-bond acceptor to a donor. This shift enables 8-oxoG to form Hoogsteen base pairs with adenine instead of cytosine, leading to its characteristic miscoding and mutagenic potential [ 117 ]. In addition to its canonical pairing with cytosine, 8-oxoG can form stable Hoogsteen base pairs with adenine, leading to G:C to T:A transversions during DNA replication [ 118 ]. Moreover, OGG1-deficient cells exhibit elevated levels of spontaneous mutagenesis [ 119 ]. Furthermore, combined deficiency of OGG1 and MYH glycosylases results in age-related accumulation of 8-oxoG in the DNA of the lungs and small intestine, with cumulative damage in the liver, ultimately increasing cancer susceptibility in Myh −/− /Ogg1 −/− mice [ 120 ]. Somatic mutations in the OGG1 gene are frequently observed in various human cancers, and the gene exhibits a high degree of polymorphism in the general population. Mutant forms of the OGG1 gene exhibit substantially reduced repair activity relative to that of the wild-type, thereby contributing to different types of tumorigenesis [ 121 ]. Moreover, when OGG1 is impaired, the equilibrium between innate and adaptive immune responses is disrupted via heightened oxidative stress and cytokine imbalances, suggesting that this is a crucial target for lung cancer treatment [ 122 ]. In gynecologic oncology, polymorphisms in the OGG1 gene have been linked to the risk and progression of cancers such as ovarian and cervical cancer. Altering OGG1 expression using gene therapy or small-molecule inhibitors can affect ovarian cancer cell growth, apoptosis, and sensitivity to chemotherapy [ 123 , 124 ]. Additionally, Xu et al. reported that decreased OGG1 expression enhances ultrasound-induced apoptosis in cervical cancer cells [ 125 ]. Ba et al. demonstrated that ROS inducers trigger parthanatos in cervical cancer cells through OGG1-catalyzed overexcision of 8-oxoG [ 80 ]. Therefore, targeting OGG1 for cancer therapy in obstetric and gynecologic malignancies warrants further in-depth investigation.

TH5487 [ 40 ] is a selective small-molecule inhibitor that interferes with the binding of OGG1 to 8-oxoG in DNA, thereby indirectly suppressing OGG1-mediated base excision repair without inhibiting its catalytic activity. This inhibition also decreases DNA occupancy by NF-κB and reduces TNF-α-induced neutrophil recruitment. Furthermore, it downregulates the expression of inflammation-related genes and limits immune cell recruitment, thereby alleviating inflammatory responses in mice. Moreover, treatment with TH5487 significantly inhibits goblet cell hyperplasia, mucus overproduction, and immune cell infiltration in a mouse model of ovalbumin-induced allergic airway inflammation. It also modulates the expression of several key genes associated with asthma pathogenesis [ 126 ]. Furthermore, TH5487 treatment leads to an increase in apoptosis and ROS generation in ovarian granulosa cells, alongside a reduction in the inflammatory responses of these cells [ 96 ]. Therefore, TH5487-based anti-inflammatory therapy may represent a promising therapeutic approach. Moreover, although oxidative products are elevated in mice lacking OGG1 activity, they do not adversely affect embryonic development, lifespan, or other major physiological outcomes. Instead, inflammation levels are significantly reduced in vivo [ 127 ]. These findings suggest that maintaining a balanced level of OGG1 activity may be beneficial for managing inflammatory disorders. Antioxidants, such as vitamin C and butylated hydroxyanisole, prevent E2-induced DNA damage in breast carcinogenesis by enhancing the binding of NRF2 to the promoter region of OGG1 gene [ 128 ]. Moreover, OGG1 depletion impairs cancer cell proliferation by inducing S-phase DNA damage, replication stress, and subsequent cell cycle arrest or apoptosis, thereby supporting OGG1 as a potential therapeutic target in cancer. Additionally, OGG1 depletion has been shown to reduce tumor growth in vivo [ 129 ]. ROS-inducing agents promote parthanatos in cervical cancer cells by inducing DNA strand breaks via OGG1-mediated excision of 8-oxoG. Furthermore, TH588—a microtubule-interacting agent and selective inhibitor of MTH1—impairs the sanitization of oxidized nucleotides, resulting in mitosis-dependent accumulation of genomic 8-oxodG and disruption of mitotic progression, thereby contributing to tumor growth suppression [ 80 ]. This approach may offer a more targeted and safer strategy for cervical cancer chemotherapy. Enzymes such as OGG1 are integral to the pathways that regulate cancer and inflammation, making them promising targets for diagnosis and future therapeutic interventions (Fig.  4 ). Fig. 4 Potential therapeutic role of targeting OGG1 in obstetric and gynecological disorders. Following oxidative stress, 7,8-dihydro-8-oxoguanine (8-oxoG) accumulates in DNA, and OGG1, along with its repair intermediates, can initiate pathological processes, including inflammation, vascular endothelial damage, and cell death. Given its central role in repairing oxidative DNA damage and modulating downstream inflammatory responses, OGG1 has emerged as a promising therapeutic target. Modulating OGG1 activity could offer therapeutic benefits for treating obstetric and gynecological conditions linked to oxidative stress and DNA damage, potentially improving outcomes in disorders such as preeclampsia, recurrent miscarriage, and endometriosis Potential therapeutic role of targeting OGG1 in obstetric and gynecological disorders. Following oxidative stress, 7,8-dihydro-8-oxoguanine (8-oxoG) accumulates in DNA, and OGG1, along with its repair intermediates, can initiate pathological processes, including inflammation, vascular endothelial damage, and cell death. Given its central role in repairing oxidative DNA damage and modulating downstream inflammatory responses, OGG1 has emerged as a promising therapeutic target. Modulating OGG1 activity could offer therapeutic benefits for treating obstetric and gynecological conditions linked to oxidative stress and DNA damage, potentially improving outcomes in disorders such as preeclampsia, recurrent miscarriage, and endometriosis

OGG1 plays a critical role in obstetric and gynecological diseases by influencing multiple pathological processes, including inflammation, vascular endothelial damage, and cell death. Its functions span DNA repair, tumorigenesis, tumor progression, and pregnancy-related complications. Although we have made every effort to comprehensively review the available literature, we acknowledge that current studies specifically focusing on OGG1 in obstetric and gynecological diseases remain relatively limited. This scarcity of research not only presents a challenge in drawing more definitive conclusions but also highlights a critical knowledge gap in the field. Therefore, our review aims not only to summarize existing evidence but also to draw attention to this underexplored area, which we believe holds significant potential for future discoveries. In-depth investigations into the roles of OGG1 and its underlying molecular mechanisms are urgently needed. Ultimately, advancing our understanding of OGG1 may facilitate the development of novel therapeutic strategies to improve patient outcomes and quality of life in gynecologic and obstetric diseases.

Reactive free radicals, including superoxide (O• −2 ), hydrogen peroxide (H 2 O 2 ), hydroxyl radicals (•OH), and peroxynitrite (ONOO − ), can damage proteins, lipids, DNA, and RNA within cells, ultimately leading to dysfunction and cell death [ 1 , 2 ]. When DNA is oxidized, it can undergo various types of damage, including base modifications (oxidized bases), strand breaks (both single and double strand), and cross-linking between strands [ 3 ]. Among all nucleic acid bases, guanine has the lowest oxidation potential, making it particularly vulnerable to reactive oxygen species (ROS). This susceptibility leads to the formation of 7,8-dihydro-8-oxoguanine (8-oxoG), a well-established marker of oxidative stress. The accumulation of 8-oxoG in DNA is considered one of the most reliable indicators of oxidative damage [ 4 ] and is frequently detected in guanine-rich promoter regions of genes [ 5 ]. Oxidative base modifications induced by ROS contribute to a variety of biological and pathological processes, including mutagenesis, carcinogenesis, neurodegeneration, and aging, thereby underscoring the central role of oxidative stress in disease development and cellular dysfunction [ 6 – 9 ]. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) primarily recognizes and excises the prominent oxidative lesion 8-oxoG in double-stranded DNA via the base excision repair (BER) pathway [ 10 ]. Additionally, OGG1 also exhibits significant activity against other oxidatively damaged bases, including 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 8-oxo-7,8-dihydroadenine (8-oxoA), though with reduced efficiency for 8-oxoA compared to 8-oxoG [ 11 – 13 ]. The BER pathway serves as the primary mechanism responsible for repairing small, non-bulky oxidative DNA lesions. OGG1 and MUTYH (MutY DNA glycosylase) are core enzymes in the 8-oxoG repair pathway. OGG1 excises 8-oxoG lesions, while MUTYH removes adenines misincorporated opposite unrepaired 8-oxoG during replication. Their collaboration prevents G:C → T:A transversions induced by oxidative damage [ 14 , 15 ]. By excising mutagenic 8-oxoG lesions from mtDNA, mitochondrial OGG1 protein safeguards genome integrity. This repair prevents mtDNA damage-driven ROS overproduction, thereby indirectly supporting cellular redox homeostasis [ 16 ]. Besides mitochondria, oxidoreductases such as NADPH oxidases and cytochrome P450 enzymes also generate ROS, contributing to redox signaling and cellular homeostasis. These ROS act as second messengers in gene expression, immunity, and aging, while their dysregulation is linked to cancer, cardiovascular disease, and neurodegeneration [ 17 – 19 ]. RNA molecules exhibit heightened susceptibility to ROS-induced oxidative damage due to converging factors: their single-stranded topology (exposing nucleobases), absence of histone shielding, rapid metabolic turnover, and proximity to endogenous ROS sources (e.g., mitochondrial electron transport chain). Moreover, the levels of 8-oxoG in RNA are 14–25 times higher than those in double-stranded DNA [ 20 ]. When mRNA is heavily oxidized, cells degrade the damaged transcripts via RNA degradation, while extensive damage at the tissue level may lead to apoptosis, respectively reflecting localized and systemic responses to oxidative stress [ 8 , 21 ]. When mRNA is heavily oxidized, cells typically degrade the damaged transcripts through RNA degradation mechanisms to preserve transcriptomic integrity. However, under sustained or severe oxidative stress at the tissue level, extensive cell injury or death may occur, leading to apoptosis and the subsequent release of oxidized nucleic acids—such as 8-oxoG-modified RNA and DNA—into the bloodstream. These extracellular oxidized nucleic acids have been proposed as potential biomarkers for oxidative stress-related conditions, including autoimmune disorders, diabetes, and cardiovascular diseases [ 22 ]. Oxidative stress is a key factor in the development and progression of several gynecological and obstetric conditions. Specifically, it contributes to diseases such as polycystic ovary syndrome [ 23 ], endometriosis [ 24 ], preeclampsia [ 25 ], preterm birth [ 26 ], ovarian cancer [ 27 ], and cervical cancer [ 28 ] through mechanisms including cellular damage, inflammatory responses, and apoptosis. Elevated ROS levels can damage DNA, leading to genetic mutations and dysfunction, which further exacerbate the pathological processes underlying these diseases. Obstetric and gynecological diseases typically involve complex pathophysiological processes, including inflammation, vascular endothelial damage, and cell death. Although OGG1 plays a crucial role in various physiological and pathological processes, comprehensive reviews summarizing its mechanistic role in obstetric and gynecological diseases remain limited. This lack of a thorough exploration underscores the need for further research to better understand the therapeutic potential of OGG1 for these conditions. In this review, the mechanisms by which OGG1 regulates inflammation, vascular endothelial damage, and cell death are summarized, emphasizing its involvement and potential as a therapeutic target in obstetric and gynecological diseases.