Endometrial senescence: inevitability and conditional occurrence in female fertility.

This work was supported by the Jilin Provincial Scientific and Technological Development Program (20240602029RC) and the Jilin Provincial Health Commission (2023LC043).

Normal cyclic senescence is initiated by progesterone and cAMP to promote decidualisation of endometrial stromal cells and facilitate embryo implantation. After embryo implantation, immune cells efficiently remove senescent stromal cells, thereby restoring normal endometrial function. In contrast, pathological excessive senescence is induced by external stimuli or ageing. The accumulation of senescent cells contributes to endometrial dysfunction and represents a key factor in RM and other gynaecological disorders. Impaired immune cell function further limits the timely clearance of senescent cells, promoting secondary senescence and exacerbating deterioration of the endometrial microenvironment. These distinctions highlight the context-dependent effects of senolytic agents, which may induce differential endometrial responses depending on timing and dosage. Consequently, senolytic therapies hold potential for the precise modulation of disease processes related to endometrial senescence, particularly when combined with immunomodulatory strategies. However, further research is required to establish their efficacy, safety and clinical applicability.

It is well established that cells respond to changes in the external environment by accelerating apoptosis or necrosis. However, Alekseenko et al. indicated that the direct response of human endometrium-derived mesenchymal stem cells (hMESCs) to external environmental stressors, such as sublethal heat shock, is premature senescence rather than apoptosis ( Alekseenko et al. 2014 ). Toropov et al. further reported that stromal cell tumours are rare, and even stromal cells overexpressing HRAS G12V cannot bypass cellular senescence and proliferate indefinitely ( Toropov et al. 2023 ). These findings suggest that cellular senescence plays a critical role in maintaining endometrial function. Cellular senescence is characterised by irreversible cell cycle arrest, DNA damage and increased expression of senescence-associated secretory phenotype (SASP) ( He & Sharpless 2017 , Han et al. 2022 ). It has also been described as developmentally programmed senescence ( Muñoz-Espín et al. 2013 ), which contributes to multiple biological processes, including organogenesis and tissue remodelling ( van Deursen 2014 , Yun et al. 2015 ). However, premature or excessive cellular senescence has been implicated in the onset and progression of various diseases, including dermatological disorders, cardiovascular diseases and neurodegeneration ( Dańczak-Pazdrowska et al. 2023 , Evangelou et al. 2023 , Melo Dos Santos et al. 2024 ). These findings indicate that cellular senescence exerts a dual effect in human biology ( Muñoz-Espín & Serrano 2014 ). The human endometrium is composed of a luminal epithelium and a surrounding matrix containing uterine glands. In the absence of an embryo, the endometrium undergoes cyclical shedding and regeneration. Upon embryo arrival, endometrial cells coordinate their functions to support implantation and early development. Su et al. found that the relative proportions of epithelial and stromal cells are critical determinants of endometrial status ( Suhorutshenko et al. 2018 ). During the window of implantation (WOI), stromal cells undergo decidualisation. Decidualised stromal cells subsequently exhibit acute senescence, characterised by the secretion of SASP and release of chemokines that recruit immune cells. This process, termed ‘normal cyclical senescence’, provides a receptive microenvironment for embryo implantation ( Brighton et al. 2017 ). After implantation, senescent decidual stromal cells are cleared by uterine natural killer (uNK) cells and other immune cells, ensuring appropriate tissue remodelling and embryo support ( van Deursen 2014 ). However, impaired clearance of senescent cells can lead to their accumulation, resulting in reduced uterine contractility and decreased expression of oestrogen receptors ( Tinelli et al. 2023 ). This pathological state has been strongly associated with recurrent implantation failure (RIF) and endometriosis ( Cha & Aronoff 2017 , Chemerinski et al. 2024 , Tang et al. 2024 ). This review outlines the differences between normal cyclical senescence and pathological excessive senescence in endometrial stromal cells (EnSCs) and discusses potential clinical intervention strategies for diseases associated with endometrial senescence, thereby offering a clear theoretical framework for future research. In recent years, an increasing number of individual genes have been identified as regulators of endometrial senescence. Mahmud et al. analysed six previously published gene sets related to cellular senescence ( Zhao et al. 2016 , Dong et al. 2017 , Gorgoulis et al. 2019 , Avelar et al. 2020 , Atlas 2021 , Saul et al. 2022 ) and identified 245 genes present in at least three gene sets, thereby providing a valuable resource for the identification of cellular senescence biomarkers ( Mahmud et al. 2024 ). Lucas et al. identified two differentiation-associated marker genes corresponding to decidual cells (DCs) and senescent decidual cells (snDCs). Scavenger receptor class A member 5 (SCARA5) exhibited peak expression in DCs, whereas deiodinase-2 (DIO2) showed peak expression in snDCs ( Lucas et al. 2020 ). In addition, P16 INK4a is a well-established marker of senescent cells and is regulated via the retinoblastoma (RB) pathway ( Rayess et al. 2012 , Martin et al. 2014 ). In the endometrial epithelial cells from women of advanced maternal age, p16 INK4a staining intensity is higher than that observed in younger women ( Loid et al. 2024 ). However, p16 INK4a -positive senescent cells are not continuously cleared. Grosse et al. demonstrated that p16-positive cells are crucial for maintaining health span in mice ( Grosse et al. 2020 ). Another key signalling pathway involved in ageing dysregulation is the p53/P21/RB signalling pathway. In mouse models, Hirota et al. found that uterine-specific knockout of p53 promotes endometrial cell senescence through the COX2/PGF2α pathway ( Hirota et al. 2010 ). In primary human stromal cell models, CDC42 deficiency activates p53/p21 and p16 signalling, thereby promoting senescence in hEnSCs ( Tang et al. 2024 ). Oxidative stress can induce senescence in hMESCs via the ATM/p53/p21 pathway. Notably, the ATM inhibitor Ku55933 enables senescent cells to escape permanent cell cycle arrest and re-enter the S phase, leading to the formation of tetraploid cells ( Borodkina et al. 2014 ). Inhibition of neddylation in hEnSCs accelerates cell senescence through excessive accumulation of p21, resulting in reduced cell proliferation and impaired decidualisation capacity. Although Si Cdkn1a can alleviate cellular senescence, it does not restore decidualisation, suggesting the involvement of additional regulatory mechanisms ( Liao et al. 2015 ). The PTEN/mTOR signalling pathway may represent one such mechanism. Both PTEN knockdown (KD) and knockout (KO) induce senescence in primary hEnSCs ( Toropov et al. 2023 , Liu et al. 2024 ). Furthermore, in a mouse model, activation of mTORC1 signalling during early pregnancy promotes preterm birth by mediating decidual cell senescence ( Hirota et al. 2011 ). Beyond gene expression, epigenetic regulation also plays a critical role in endometrial cellular senescence and may serve as a predictive marker for the progression of endometrial lesions ( Deryabin & Borodkina 2023 ). The senescence-associated secretory phenotype (SASP) represents an important class of biomarkers associated with endometrial cellular senescence. SASP can mediate secondary senescence, whereby senescent cells induce senescence in neighbouring non-senescent cells through paracrine signalling, a phenomenon also referred to as the ‘bystander effect’ ( Vassilieva et al. 2018 ). SASP comprises a diverse range of bioactive factors, including interleukins (IL-6, IL-8, IL-1α and IL-1β), transforming growth factor-β (TGF-β), fibroblast growth factors (FGFs), matrix metalloproteinases (MMP-1, MMP-3 and MMP-10) and extracellular vesicles ( Borodkina et al. 2018 ). Interleukin 17B (IL-17B) has been shown to upregulate the expression of IL-6, IL-8 and IL-1β. Elevated IL-1β levels can inhibit cellular proliferation in endometrial tissue and accelerate cell senescence via activation of the JNK signalling pathway ( Kawamura et al. 2024 , Taylor et al. 2024 ). In addition, uterine tissue-specific SASP components have been identified ( Fig. 1 ). Vassilieva et al. showed that senescent hEnSCs secrete IGF-binding protein 3 (IGFBP3) via the PI3K/Akt signalling pathway and that increased expression of IGFBP3 promotes senescence in adjacent cells ( Vassilieva et al. 2020 ). Griukova et al. found that secretion of plasminogen activator inhibitor-1 (PAI-1) is significantly increased in hEnSCs. Deletion of the SERPINE-1 gene, which encodes PAI-1, attenuates the induction of senescence in neighbouring cells, indicating that PAI-1 plays a key role in mediating the propagation of senescence in hEnSCs ( Griukova et al. 2019 ). Collectively, these findings suggest that specific gene expression changes induce senescence in endometrial stromal cells, which subsequently secrete SASP factors, containing IL-6, IGFBP3 and PAI-1, thereby promoting senescence in surrounding stromal cells ( Fig. 1 ). Senescence transmission in EnSCs. Abnormal gene expression, oxidative stress damage or advanced maternal age can easily induce normal EnSCs (shown in white) to transform into primary senescent cells (shown in blue, the depth of blue represents the degree of senescence). Primary senescent EnSCs secrete senescence-associated secretory phenotypes (SASP, shown as dots) including IL-6, IGFBP3 and PAI-1, which infect surrounding young cells in a paracrine manner for secondary senescence. In addition to the classical senescent markers described above, several molecules are differentially expressed in the endometrium across age groups and may serve as potential biomarkers of endometrial senescence. Devesa-Peiro et al. reported that age is an important factor influencing genes related to endometrial senescence, including those involved in cell cycle arrest and DNA repair inhibition ( Devesa-Peiro et al. 2022 , Pathare et al. 2023 ). It is well established that female fertility declines with advancing age ( Baird et al. 2005 , Nelson et al. 2013 ). Implantation rates also decrease significantly with increasing age, even in embryo transfer cycles using donor oocytes, while miscarriage rates increase in women older than 40 years ( Cano et al. 1995 , Sherbahn 2008 ). Kawamura et al. identified IL17RB, CXCL12 and CXCL14 as candidate genes associated with endometrial cell senescence, with significantly higher expression in the secretory endometrium of women aged 40 years compared with those aged 20 years ( Kawamura et al. 2020 ). Wang et al. further demonstrated a synergistic interaction between H3K27ac and progesterone receptor (PGR), contributing to reduced endometrial receptivity in women older than 35 years ( Wang et al. 2025 ). In addition, the PI3K–AKT–FOXO1 signalling pathway is overactivated in age-related senescent endometrium. Modulation of this pathway has been shown to alleviate fibrosis and improve endometrial receptivity in organoids derived from women of advanced reproductive age (≥35 years) ( Lu et al. 2025 ). Taken together, multiple signalling pathways contribute to endometrial senescence, acting either independently or synergistically. However, most currently identified biomarkers remain general markers of cellular senescence rather than endometrium-specific indicators. Notably, Liao et al. demonstrated that knockdown of p21 restores stromal cell proliferation but does not recover the specialised decidualisation capacity of EnSCs ( Liao et al. 2015 ). At present, no standardised biomarkers or diagnostic criteria for endometrial senescence have been established in clinical practice, and the biological age of the endometrium does not necessarily correspond to chronological age. Therefore, there is an urgent need to develop a robust evaluation system for accurately assessing endometrial senescence. In addition, the mechanisms underlying senescence propagation between different cell types within endometrial tissues remain poorly understood. Further studies are required to identify specific and clinically applicable biomarkers of endometrial senescence. During the proliferative phase of the human endometrium, oestrogen levels gradually increase, accompanied by upregulation of oestrogen receptor alpha (ERα/ ESR1), which stimulates stromal cell proliferation ( Critchley et al. 2020 ). Activation of ERα promotes angiogenesis, thereby supporting stromal cell expansion through enhanced nutrient and energy supply ( Yu et al. 2014 ). In the secretory phase, hEnSCs undergo morphological transformation, becoming rounded and exhibiting reduced stiffness and surface roughness, ultimately differentiating into decidualised stromal cells. This process facilitates endometrial remodelling to suppress maternal immune rejection and prepares the uterus for embryo implantation ( Pan-Castillo et al. 2018 , Meng et al. 2023 ). Through decidualisation, the endometrium changes from a non-receptive state to a receptive state, and the ‘WOI’ transiently opens to allow embryo implantation ( Karizbodagh et al. 2017 , Vasquez et al. 2018 ). Oestrogen and progesterone mediate decidualisation of stromal cells by promoting NF-κB-mediated inflammatory responses, thereby enhancing endometrial receptivity ( Evans & Salamonsen 2014 ). Progesterone also regulates the BMP2/Wnt signalling pathway through the progesterone receptor and promotes decidualisation ( Li et al. 2007 , Franco et al. 2011 , Nallasamy et al. 2019 ). In mouse models, deletion of the BMP2 gene results in infertility due to failure of stromal cell differentiation; embryos adhere only to the endometrial epithelial cells and fail to implant ( Paria et al. 2001 ). Recent studies have identified SETD7 as a novel regulator of decidualisation, with its expression significantly correlated with the SCARA5/DIO2 ratio ( Konyushatova et al. 2025 ). In addition, cyclic adenosine monophosphate (cAMP) and FOXO1 are important components in the initiation of decidual senescence ( Gellersen & Brosens 2014 ). Upon cAMP stimulation, FOXO1 binds to C/EBP-β in a PKA-dependent manner, promoting the expression of prolactin (PRL) and insulin growth factor-binding protein 1 (IGFBP1) and decidualisation of EnSCs ( Deryabin et al. 2020 , Adiguzel & Celik-Ozenci 2021 ). Furthermore, Kendirci-Katirci et al. proposed that the FOXO1–DIO2 signalling plays a critical role in initiating senescence of decidual stromal cells during the early stage of pregnancy ( Kendirci-Katirci et al. 2024 ). Additional regulators, including BMP4, PGRMC1 and SIRT1, have also been shown to modulate stromal cell senescence through regulation of FOXO1 ( Tsuru et al. 2022 , Yu et al. 2022 , Huang et al. 2024 ). Following embryo implantation, senescent decidual stromal cells are precisely cleared by immune cells. Natural killer (NK) cells secrete cytotoxic granules containing perforin and granzyme. Perforin forms pores in the plasma membrane of target cells, enabling the entry of particles into the cytoplasm, thereby triggering apoptosis of senescent cells ( Sagiv & Krizhanovsky 2013 , Antonangeli et al. 2019 ). CD44, a receptor for hyaluronan (HA), mediates the cytotoxic activity of uterine NK (uNK) cells against senescent decidualised cells. High-molecular-weight HA, in contrast to low-molecular-weight HA, inhibits uNK cell activity. Recombinant hyaluronidase 2 (HYAL2) degrades high-molecular-weight HA and restores the ability of uNK cells to clear senescent decidualised cells ( Kong et al. 2021 ). Similarly, Egashira et al. demonstrated that F4/80+ macrophages and CD11b + cells regulate the immune microenvironment, promote clearance of senescent cells in the postpartum uterus and contribute to endometrial remodelling in p53-deficient mice ( Egashira et al. 2017 ). More recently, Shi et al. demonstrated that TNFSF14 + NK cells can inhibit decidual stromal cell senescence by limiting leucine accumulation, thereby reducing the risk of spontaneous abortion in mice ( Shi et al. 2024 ). Collectively, these findings suggest that senescence in endometrial stromal cells can be partially reversed or controlled by immune cells, including uNK cells and macrophages. This immune-mediated clearance represents a critical step in normal cyclical senescence and is essential for successful embryo implantation and pregnancy ( Fig. 2 ). Clearance of senescent endometrial stromal cells through uNK cells. Hyaluronic acid (HA) exists in two forms: high-molecular-weight HA (HMWHA, presenting as long and coiled chains) and low-molecular-weight HA (LMWHA, presenting as shorter fragments). The cell surface receptor CD44 on uterine natural killer cells (uNK) binds to low-molecular-weight hyaluronic acid, which can reverse the senescence of EnSCs. Macrophages also have a similar function. CD44 binds to high-molecular-weight HA, promoting the senescence of EnSCs. After HYAL2 decomposes high-molecular-weight HA, it can reverse the senescence phenotype. Each new cell or protein represented by a graphic is marked below the picture. Age is an important determinant of endometrial senescence; however, it has also been reported that patients with RIF under 35 years of age exhibit poorer pregnancy outcomes when the endometrium is senescent compared with non-senescent endometrium ( Chen et al. 2022 ). These findings suggest that age-dependent endometrial senescence contributes to endometrial dysfunction and may underlie various infertility-related disorders. RIF is defined as the failure to achieve a clinical pregnancy after transfer of at least four high-quality embryos across a minimum of three cycles ( Coughlan et al. 2014 ). Impaired endometrial receptivity is considered a major cause of implantation failure, accounting for approximately 30% of cases ( Tomari et al. 2020 , Makrigiannakis et al. 2021 ). Excessive senescence of endometrial cells is a key contributor to reduced endometrial receptivity. Deryabin et al. reported that 57 receptivity-associated markers are dysregulated in senescent stromal cells. In addition, extracellular matrix degradation, impaired interactions between senescent stromal cells and extravillous trophoblasts and restricted trophoblast invasion during the WOI were observed ( Deryabin & Borodkina 2022 ). In a related study, Deryabin et al. demonstrated that reduced expression of antioxidant defence genes, together with elevated intracellular and mitochondrial reactive oxygen species (ROS) levels in senescent stromal cells, disrupt trophoblast cell integrity ( Deryabin et al. 2022 ). Tomari et al. found that the proportion of senescent cells is significantly higher in non-receptive patients (defined as those who fail to achieve pregnancy following embryo transfer) compared with receptive patients (those who achieve pregnancy) ( Tomari et al. 2020 ). Collectively, these results indicate that excessive senescence of EnSCs impairs endometrial receptivity and adversely affects embryo implantation. Recurrent miscarriage (RM) is defined as the occurrence of two or more clinical pregnancy failures ( Practice Committee of the American Society for Reproductive Medicine 2012 ). Lucas et al. reported that endometrial biopsies from patients with RM showed higher DIO2 expression than the control group, indicating an increased burden of senescent endometrial cells ( Lucas et al. 2020 ). Endometriosis is a major cause of infertility and pelvic pain, affecting more than 10% of women worldwide. Compared with healthy controls, the proportion of IGFBP1 + decidual stromal cell subsets among shed EnSCs from patients with endometriosis is significantly reduced, whereas a greater proportion of stromal cells exhibit inflammatory and senescent phenotypes ( Shih et al. 2022 ). In addition, Malvezzi et al. also found that the expression of IL-4 and IL-1β is elevated in ectopic endometrium compared with eutopic endometrium ( Malvezzi et al. 2022 ). Recent evidence showed that azithromycin (AZM) may help prevent the progression of endometriosis by suppressing SASP-associated IL-6 secretion ( Sonehara et al. 2025 ). These results indicate that excessive senescence of EnSCs is associated with RM, RIF and endometriosis. Cheloufi et al. found that dysregulation of the immune microenvironment contributes to both RIF and RM, and targeted immunotherapy may significantly improve live birth rates ( Cheloufi et al. 2021 ). In the normal endometrium, the number of senescent stromal cells (P16-positive cells) is positively correlated with multiple immune cells. However, in patients with RIF, this correlation is weakened for CD4 + cells and CD8 + cells and is absent for CD68 + macrophages, CD14 + monocytes and CD79a + B cells ( Parvanov et al. 2023 ). Furthermore, Brighton et al. reported that deficiency of uNK cells contributes to secondary senescence ( Brighton et al. 2017 ). Insufficient, rather than excessive, activation of uNK may underlie RM and RIF ( Alecsandru et al. 2020 ). Consistent with these findings, patients with RM and endometriosis exhibit reduced uNK cell abundance and an increased number of senescent cells compared with controls. Co-culture of EnSCs with uNK cells has been shown to partially reverse the senescent process ( Lucas et al. 2020 , Shih et al. 2022 ). Additionally, Jia et al. showed that combining endometrial receptivity analysis with immunoassay provides enhanced clinical value for the diagnosis and treatment of RIF ( Jia et al. 2022 ). There are significant differences between pathological excessive senescence and normal cyclical senescence in terms of initiating factors, implantation outcomes and immune regulation. Normal cyclical senescence is initiated by progesterone and cAMP, which improve endometrial receptivity and create an environment conducive to embryo implantation. Subsequently, immune cell activation facilitates the clearance of senescent cells and restores the normal endometrial state. In contrast, pathological excessive senescence is driven by excessive external stimuli, such as oxidative stress, ageing and abnormal gene expression. The accumulation of senescent stromal cells disrupts the endometrial function and impairs embryo implantation. SASP factors released by senescent cells can propagate senescence to neighbouring endometrial stromal cells. Concurrently, insufficient activation of immune cells limits the clearance of senescent stromal cells, leading to their progressive accumulation ( Fig. 3 ). Comparison of normal cyclical senescence and pathological excessive senescence. The normal cyclical senescence process of the endometrium is shown in green on the left, and the pathological excessive senescence process of the endometrium is shown in blue on the right. The differences in initiating factors, embryo implantation, immune clearance and endometrial outcomes between the two types of endometrial senescence were shown. Normal cyclical senescence is initiated by progesterone /cAMP. The senescence of EnSCs provides better endometrial receptivity for embryos. After the completion of embryo implantation, immune cells clear the senescent EnSCs and the endometrium recovers as normal. Pathological excessive senescence is initiated by external factors such as oxidative stress. Excessive senescence of EnSCs leads to impaired endometrial function, embryo failure to implant, insufficient number or insufficient activation of immune cells, senescence of EnSCs cannot be eliminated, and eventually endometrial senescence accumulates. Decidualisation is a complex, multi-step differentiation process. During decidualisation, EnSCs exhibit reduced proliferation retarding and secrete components of SASP ( Kusama et al. 2021 ). Transient exposure to SASP has been shown to increase the expression of stem cell-related genes, enhance cellular plasticity and promote tissue regeneration. In contrast, prolonged exposure to SASP induces secondary senescence in neighbouring cells ( Ritschka et al. 2017 ). Senolytic drugs, such as dasatinib, quercetin, rapamycin, deferoxamine (DFO), resveratrol and dimethyldiguanide, have been reported to attenuate ageing-related processes by targeting SASP without affecting the cell cycle of normal cells ( Lagoumtzi & Chondrogianni 2021 ). In hMESCs, DFO pretreatment prevents oxidative stress-induced premature senescence while preserving cellular function ( Griukova et al. 2018 , Shatrova et al. 2021 ). Multiple studies have shown that senolytic drugs exert stage-dependent effects on stromal cells during decidualisation. Kuroda et al. found that senolytic drugs, such as dasatinib, rapamycin and resveratrol, can inhibit decidualisation when administered at early stages, either by preventing the emergence of senescent cells or by eliminating them prematurely ( Kuroda et al. 2020 ). Similarly, Ochiai et al. reported that resveratrol inhibits decidualisation at its onset by interfering with retinoic acid signalling ( Ochiai et al. 2019 ). Conversely, excessive or dysregulated senescence during decidualisation can impair endometrial receptivity, and targeted reduction of senescence in EnSCs may alleviate implantation dysfunction ( Kusama et al. 2021 ). Dasatinib pretreatment eliminates decidual senescence and accelerates decidualisation in an endometrial assembly model ( Rawlings et al. 2021 ). Quercetin enhances decidualisation via the AKT-ERK-p53 signalling pathway ( Delenko et al. 2024 ). Combined treatment with dasatinib and quercetin further promotes decidualisation by removing senescent decidua cells, with greater efficacy than either agent alone. However, BPTES [bis-2-(5-phenyl-acetamido-1,3,4-thiadiazol-2-yl) ethyl sulphide], which is associated with the survival of senescent cells, does not enhance the expression of decidualisation markers ( Kusama et al. 2021 ). Furthermore, pretreatment of senescent hEnSCs with dimethyldiguanide or rapamycin promotes decidualisation and facilitates blastocyst implantation ( Deryabin & Borodkina 2022 ). Collectively, these findings suggest that endometrial decidualisation is modulated by the bidirectional effects of senolytic agents. In recent years, endometrial senescence has attracted increasing attention in reproductive medicine. However, given the specificity of senolytic agents and the complex, context-dependent role of senescence in the endometrium, no senolytic drugs have been approved for use in assisted reproductive technology or routine clinical practice to improve infertility associated with endometrial disorders. In addition, most existing studies investigating the effect of senolytic agents on endometrial senescence are based on in vitro experiments. Traditional two-dimensional (2D) cell culture models are limited in their ability to accurately recapitulate the complex cellular interactions and cyclical changes of the human endometrium. Organoid technology, which has been widely used in tissues such as the intestine and brain, has recently been extended to the development of endometrial organoids ( Yoneda et al. 2026 ). Future studies should focus on utilising three-dimensional (3D) organoids derived from patient endometrial stem cells to better model endometrial physiology and pathology and to evaluate the therapeutic potential of senolytic drugs in alleviating endometrial dysfunction. Although several senolytic drugs are currently available for treatment of other conditions and have demonstrated favourable safety profiles ( Sanchez-Rangel & Inzucchi 2017 , Fauziya et al. 2023 ), the optimal timing and dosage regimens for their application in endometrial contexts remain to be established. In addition to alleviating endometrial disorders associated with cellular senescence, senolytic agents may also promote decidualisation. However, variations in the timing and dosage of administration can result in distinct endometrial responses. This dual and context-dependent effect suggests that senolytic therapies could be utilised to more precisely regulate disease processes associated with endometrial senescence. Furthermore, combining senolytic therapies with immunotherapeutic approaches may offer additional clinical benefits. Nevertheless, further studies are required to elucidate the efficacy, safety and clinical applicability of such strategies.

The authors declare that they have no known competing financial or personal interests that could have appeared to influence the work reported in this paper.

CN contributed to conceptualisation, visualisation and writing of the original draft. X Lin contributed to conceptualisation and funding acquisition. LL and JF contributed to formal analysis. X Lu contributed to supervision. QW contributed to validation. HW and SL contributed to methodology. YM contributed to visualisation. LC contributed to investigation and methodology. XM and YF contributed to funding acquisition, supervision and review and editing of the manuscript.