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The Roles of Placental Senescence, Autophagy and Senotherapeutics in the Development and Prevention of Pre-Eclampsia: A Focus on Ergothioneine

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Submitted:

14 April 2025

Posted:

15 April 2025

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Abstract
Cellular senescence is a well-established biological phenomenon in eukaryotes. It involves DNA damage, telomere shortening, a senescence-associated secretory phenotype (SASP), and the inability of cells to replicate. It is associated with ageing, and also with oxidative stress. Given the importance of oxidative stress in pre-eclampsia, there is considerable evidence, that we review, that senescence plays an important role in both normal placental development and in the development of both early- and late-term pre-eclampsia. Autophagy is capable of delaying or even reversing the development of senescence, and certain small molecules such as sulforaphane and spermidine can stimulate autophagy, including via the redox-sensitive transcription factor Nrf2. Ergothioneine is a thiohistidine antioxidant that is protective against a variety of cardiovascular and other diseases. Ergothioneine also interacts with Nrf2, and pre-eclampsia occurs far less frequently in individuals with higher plasma ergothioneine levels. Together, these elements provides a self-consistent, molecular and systems biology explanation for at least one mechanism by which ergothioneine may be protective against pre-eclampsia.
Keywords: 
pre-eclampsia
;  
ergothioneine
;  
nutraceuticals
;  
senescence
;  
autophagy
Subject: 
Biology and Life Sciences  -   Biochemistry and Molecular Biology

1. Introduction

Pre-eclampsia (PE) remains one of the most dangerous disorders of pregnancy (Poon et al. 2019, Dimitriadis et al. 2023), especially in low- and middle-income countries (Gemechu et al. 2020, Machano and Joho 2020). It also creates a strong pre-disposition to later cardiovascular events (Staff et al. 2016, Leon et al. 2019). While the initiating causes of pre-eclampsia remain uncertain (Kell and Kenny 2016, Kenny and Kell 2018), it is broadly accepted that placental oxidative stress is a major mechanistic contributor (e.g., (Raijmakers et al. 2004, Raijmakers et al. 2005, Aouache et al. 2018, Redman et al. 2022)). Unsurprisingly, given the chemistry of reactive oxygen species generation (Kell 2009, Kell 2010, Kell and Pretorius 2018), poorly liganded iron is also often involved in the generation of such oxidative stress (Ng et al. 2019, Erlandsson et al. 2021, Chen et al. 2022, Liao et al. 2022, Gumilar et al. 2023, Li et al. 2023a, Shan et al. 2023, Ortega et al. 2024, Zhang et al. 2024a).
It is customary to discriminate early (<34 weeks) and later (>34 weeks) pre-eclampsia given the differential associations with morbidity and mortality. Thus, the two-stage pre-eclampsia model of poor placentation followed by oxidative stress, as originally proposed by Redman (Redman 1991), has been refined (Redman et al. 2014, Redman and Staff 2015, Staff 2019, Redman et al. 2022) to recognise that later pre-eclampsia arises not from an initial poor placentation but from a later placental insufficiency, albeit that both mechanisms converge on oxidative stress. In this sense, pre-eclampsia shares a number of features with ME/CFS and (Long) COVID (Jayaram et al. 2021), where endothelial dysfunction (Nunes et al. 2023, Nunes et al. 2024, Kruger et al. 2025), oxidative stress (Kell et al. 2022, Kell and Pretorius 2022), a tendency to later cardiovascular diseases (Aden et al. 2022, Raman et al. 2022, Santoro et al. 2023), and an ageing phenotype (Shafqat et al. 2024) are also major features. In this sense, it is particularly noteworthy that senescence can be induced by viruses.
Originating from Hayflick’s observations of a finite replicative limit in diploid cells (Hayflick 1961), the term ‘cellular senescence’ is nowadays used to describe a stable and nominally terminal state of growth arrest in which cells are unable to proliferate despite optimal growth and signalling conditions (e.g., (Kovacic et al. 2011a, Kovacic et al. 2011b, Kirkland and Tchkonia 2017, Di Micco et al. 2021, Kajdy et al. 2021, Chaib et al. 2022, de Magalhães 2024, Shaikh et al. 2024, Wai et al. 2024, Zhu et al. 2024)). Although commonly associated with ageing and cancer (Roberts et al. 2022, López-Otín et al. 2023, O’Sullivan et al. 2024), infection can also be a trigger (Miller et al. 2024). Thus, conversion to senescence may result from replicative-, DNA damage-, oncogene-, or virus-induced mechanisms; senescence of cells in the surrounding environment may then be perpetuated through paracrine effects (Nelson et al. 2012, Nelson et al. 2018).
Among the many hallmarks of senescence, a chief one is telomere shortening (Herbig et al. 2004, Jiang et al. 2007, Rossiello et al. 2022, Suvakov et al. 2023). Another is the presence of persistent DNA damage (Huang and Zhou 2021, Kell et al. 2023), which can be probed by measuring the activation and/or localisation of proteins involved in the DNA Damage Response (DDR) pathways, such as γH2AX (histone variant H2AX phosphorylated at Ser139), p53-binding protein 1 (53BP1), and the phosphorylation of DDR master regulators, ATM (at Ser1981) and ATR (at Thr1989). Yet another involves the secretion of multiple pro-inflammatory and tissue-remodelling proteins, referred to collectively as the senescence-associated secretory phenotype or SASP (e.g., (Coppé et al. 2008, Rodier et al. 2009, Young and Narita 2009, Salminen et al. 2012, Tchkonia et al. 2013, Birch and Gil 2020, Sun et al. 2022, Kell et al. 2023)). Finally, senescent cells possess high levels and activity of the lysosomal enzyme beta-galactosidase, termed senescence-associated beta-galactosidase (SA-β-gal), thus providing another histological biomarker for assessment of cell senescence in culture and in tissues (Dimri et al. 1995, Lee et al. 2006). Overall, this offers a series of biomarkers for the presence of senescence (see also Figure 1 and Table 1). Finally, mitochondrial dysfunction is intimately involved (Passos et al. 2010, Correia-Melo et al. 2016).
Thus, characteristics of senescent cells are that they may be flattened, they possess a prominent nucleus (including a loss of nuclear membrane integrity through decreased lamin B1 expression), they lose proliferation associated with high expression of cyclin kinase inhibitors (e.g., p21, p16), they exhibit a chronic DNA damage response, senescence-associated beta-galactosidase, a loss of proteostasis/dysregulated autophagy, and a hypersecretory phenotype.
Genotoxic insults, e.g., (and of particular relevance) oxidative stress, are important inducers of the senescent phenotype (e.g., (von Zglinicki 2000, Salminen et al. 2012, Kell et al. 2023)). Consequently, the question then arises as to whether the dysfunctional or stressed state of placental tissues during the development of pre-eclampsia (and indeed to a lesser degree in normal placentae (Cox and Redman 2017)) might also reflect a senescent phenotype, and the answer is resoundingly in the affirmative (Farladansky-Gershnabel et al. 2019, Suvakov et al. 2019, Scaife et al. 2021, Tasta et al. 2021, Hu et al. 2022, Li et al. 2022, Negre-Salvayre et al. 2022, Wang et al. 2022, Zhong et al. 2022, Suvakov et al. 2023, Roh et al. 2024, Sugulle et al. 2024, Suvakov et al. 2024, Zhang et al. 2024b, Peng et al. 2025).
The first purpose of this paper, given an excellent recent review (Sugulle et al. 2024), is briefly to rehearse some of the evidence for the existence of a senescent phenotype in PE. Senescence is commonly caused by a failure or dysregulation of normal autophagy (e.g., (Kang et al. 2011)). Thus, the thrust of the rest of the review is, in the light of this evidence, to look at the potential roles of autophagy in pre-eclampsia, and finally to use this knowledge to seek small molecules that might affect senescence or autophagy and thus act as preventives of the development of PE. We recognise the uses of both spermidine and various Traditional Chinese Medicines as able to stimulate autophagy, not least via the transcription factor Nrf2 (see later). Finally, and in particular, we seek to explain mechanistically the strong protection seen to be given against pre-eclampsia and other cardiovascular diseases by the natural product ergothioneine, a known Nrf2 stimulant.
Systems analysis as applied to biology (e.g., (Kitano 2002, Hood 2003, Klipp et al. 2005, Alon 2006, Palsson 2006) describes an approach with four stages, in which the first two steps (Kell 2006a, Kell 2006b, Kell and Knowles 2006) involve (i) identifying the main players in a biological process of interest, and (ii) the qualitative interactions between them. The later steps (e.g., (Kell 2006a, Kell 2006b, Kell and Knowles 2006)) seek to understand the local kinetic rate equations describing those interactions, and then the parameterisation of those equations. At the present state of knowledge we are necessarily seeking to solve the first two steps. To this end, Figure 2 provides a qualitative systems biology diagram setting out the mechanistic and/or regulatory interactions that we see to be involved in early- and late-term pre-eclampsia, while what follows in the body of this article sets out the evidence for them.

2. Cellular Senescence in Pre-Eclampsia

We recognise that some level of senescence clearly accompanies normal, healthy pregnancy as part of placental development (e.g., (Chuprin et al. 2013, Velicky et al. 2018, Gal et al. 2019, Higuchi et al. 2019, Singh and Singh 2024)), and that severe senescence inhibition (e.g., in p53-/- and Cdkn2a-/- knockout mice (Gal et al. 2019)) leads to defects in placental growth and function As yet, we do not really know the full details of how senescence differs between normal and pathological placental development, much as in the change discussed above in the belief that poor placentation accompanied all PE when it is really just early PE. This said, the easiest way to adduce evidence for the role of excessive cellular senescence in pre-eclampsia is to look for the characteristic biomarkers of cellular senescence in PE placentas compared to those from normotensive, healthy pregnancies. Table 1 provides a summary of some of the papers that have studied these.
While senescence can be induced by a variety of means, not least by oxidative stress (Kang et al. 2011), the weight and variety of evidence summarised in Table 1 now leaves little room for doubt that placental senescence plays a considerable role in normal pregnancy, while an exacerbation of senescence through oxidative stress is observed in the development of pre-eclampsia.

3. The Roles of Autophagy in Senescence and Its Inhibition

In some senses (Kwon et al. 2017, Rajendran et al. 2019), a flipside of senescence is autophagy (Kang et al. 2011, García-Prat et al. 2016, Doherty and Baehrecke 2018, Hofer et al. 2022, Liu et al. 2023b), as autophagy is commonly dysregulated in senescence (Leidal et al. 2018, Patel et al. 2020, Cassidy and Narita 2022, Li et al. 2023b, Sehrawat et al. 2023). Autophagy describes a series of biological phenomena in which specific catabolic processes involved in cellular homeostasis serve to maintain normal cellular physiology under conditions of stress (e.g., (Eisenberg et al. 2009, Khandia et al. 2019, Liang et al. 2020, López-Otín et al. 2023)). In particular, autophagy is responsible for delivering protein aggregates and/or damaged organelles to lysosomes for degradation and nutrient recycling. It involves the enclosure of targets inside a double-membrane-bound structure, the autophagosome. This fuses with the lysosome, exposing its contents to both a low pH and the necessary degradative enzymes, breaking macromolecules down into their monomers. In general, it is seen as good for improving cellular and organismal longevity, although in excess it can be harmful (Rao and Jackson 2016, Wang et al. 2016, Liang et al. 2020).
We note that many markers do not really measure autophagic flux, which is what really matters, and that this is most commonly done by measuring the accumulation of autophagosome-bound LC3 in cells treated with an autophagy inhibitor, e.g., bafilomycin A1, compared to vehicle-treated control cells from the same sample (Tanida et al. 2008, Hanna et al. 2012, Alsaleh et al. 2020). This said, it is to be noted that Saito and colleagues (e.g., (Nakashima et al. 2013, Saito and Nakashima 2013, Saito and Nakashima 2014, Nakashima et al. 2017a, Nakashima et al. 2017b, Nakashima et al. 2020a, Nakashima et al. 2020b, Cheng et al. 2022, Huang et al. 2024, Nakashima et al. 2024)), as well as others (Table 1 and (Xiao et al. 2025)), have pointed out the potential roles of autophagy in modulating pre-eclampsia.
We also recognise that there is likely to be an optimal degree of autophagy in decreasing the incidence of pre-eclampsia, and how this is achieved is thus important. Consequently, our interest here lies in the potential for certain small molecules to stimulate autophagy safely (such molecules can also be used to delay ageing and thus act as geroprotectors (Moskalev et al. 2017)), as well as their potential use in the prevention or at least delay of the onset of pre-eclampsia.

4. Senomorphics and Senolytics

As phrased by (Lagoumtzi and Chondrogianni 2021), “Senotherapeutics is a new class of drugs and natural products that consist of two members; senomorphics and senolytics. Their main target is to eliminate or delay the adverse effects of cellular senescence and consequently, the process of aging and age-related pathologies.” Recent reviews include (Martel et al. 2020, Okuno et al. 2020, Lagoumtzi and Chondrogianni 2021, Miller et al. 2023, Zhang et al. 2023b, Zheng et al. 2024). Senolytics are compounds that selectively eliminate senescent cells, while senomorphics are compounds that modulate their behaviour. Early senolytics act by inducing apoptosis, and are widely seen as having the ability to increase the healthspan in a variety of organisms from C. elegans to mammals (Leidal et al. 2018, Chaib et al. 2022). Senomorphics tend to lower the induction of senescence by suppressing inflammatory SASP expression via the targeting of signalling pathways such as NF-kB, mTOR, IL-1a, and p38 MAPK (Zhang et al. 2023b). At this stage, it is not immediately clear which class of senotherapeutics is more likely to include the kind of modifier we seek, and this may well be an important distinction to be made. Senomorphics may be preferred over senolytics when removal of senescent cells with structural roles is deleterious, as is the case with senescent liver sinusoidal endothelial cells (Grosse et al. 2020). Understanding the replaceability of senescent trophoblasts with non-senescent types after senolytic treatment would therefore be informative. Furthermore, if studies suggest that the SASP predominantly underscores PE pathology, then senomorphics that dampen pro-inflammatory signalling pathways may be beneficial.

5. The Role of Nrf2 in Autophagy and Cytoprotection

Nuclear Factor Erythroid 2–Related Factor 2 (Nrf2) is a basic leucine zipper protein that acts as a transcription factor (Vriend and Reiter 2015, Robledinos-Antón et al. 2019, Tantengco et al. 2021b, Zhang et al. 2021b, Datta et al. 2022, Kryszczuk and Kowalczuk 2022, Muchtaridi et al. 2022, Qin et al. 2022, Egbujor et al. 2023, McCord et al. 2023, Qin et al. 2023, Wai et al. 2024), specifically activating antioxidant response elements (AREs) (e.g., (Zhang et al. 2010, Vomhof-Dekrey and Picklo 2012, Vriend and Reiter 2015, Kavian et al. 2018, Raghunath et al. 2018, Robertson 2023, Tamaru et al. 2024)) that are heavily involved in cytoprotection. Importantly, Nrf2 can itself be activated (by removing its binding to the cytoplasmic redox sensor Kelch-like ECH-associated protein 1 (Keap1)(Mutter et al. 2015, Vriend and Reiter 2015, Qin et al. 2019, Fakhri et al. 2020, Singh et al. 2021, Zhang et al. 2021b, Muchtaridi et al. 2022, Ghasemzadeh Rahbardar and Hosseinzadeh 2023, Tossetta et al. 2023, Zhang et al. 2023a, Shah et al. 2024)), leading to its translocation to the nucleus (Figure 3).
We next note that a considerable body of evidence has pointed to important roles for Nrf2 in the delay or prevention of pre-eclampsia (Table 2).
Mostly the upregulation of Nrf2 is beneficial, but in some mouse models (Nezu et al. 2017, Li et al. 2020), that may of course not reflect human pre-eclampsia, it is seemingly inactivation that helps. It is also unclear how much these properties may differ between early and late PE, as that distinction is normally not made in these mouse models.
A variety of natural products (Eggler et al. 2008, Fakhri et al. 2020, Li et al. 2021, Yarmohammadi et al. 2021, Moratilla-Rivera et al. 2023) and pharmaceuticals (Dinkova-Kostova and Copple 2023) are known to interact with Nrf2. However, our interest here lies in part in the ability of small molecules that are found in food, such as spermidine and ergothioneine, to interact with Nrf2 and to exhibit desirable biological effects. It is of interest too that pentacyclic triterpenoids including celastrol (Seo et al. 2011, Divya et al. 2016, Li et al. 2017, Luo et al. 2017, Tseng et al. 2017, Zhou et al. 2019, Zhang et al. 2021a, Younis and Ghanim 2022, Cao et al. 2023, Pan et al. 2023, Qing et al. 2023, An et al. 2024, Liu et al. 2024a), Oleanolic acid (Liu et al. 2008, Reisman et al. 2009, Wang et al. 2010, Castellano et al. 2013, Wang et al. 2013, Chung et al. 2014, Liu et al. 2022a, Alqrad et al. 2023, Liu et al. 2023a) and Ursolic acic (Li et al. 2013, Ma et al. 2015, Wang et al. 2018, Proshkina et al. 2020, Li et al. 2021, Fu et al. 2023, Wang et al. 2024b, Yang et al. 2024b) also serve to stimulate Nrf2. Finally, here, we note too that the nutraceutical kynurenic acid (Tóth et al. 2021, Turska et al. 2022, Alves et al. 2024) also increases Nrf2 activity (Bansal et al. 2019, Zhao et al. 2021, Gao et al. 2023, Misztal et al. 2024, Liu et al. 2025a).

6. Spermine and Spermidine as Geroprotectors

Sulforaphane has been widely discussed as an inducer of autophagy (e.g., (Herman-Antosiewicz et al. 2006, Yang et al. 2018, Lu et al. 2021), that also acts an activator of Nrf2 (Houghton et al. 2016, Kubo et al. 2017, Su et al. 2018, Uddin et al. 2020, Shah et al. 2024). As mentioned, two molecules of special interest in this context include the polyamines spermine and the more established spermidine, since in many circumstances they seem largely to stimulate autophagy and/or delay senescence (via a variety of mechanisms) (Madeo et al. 2010, Puleston et al. 2014, Puleston and Simon 2015, Tong and Hill 2017, Zhang et al. 2019, Alsaleh et al. 2020, Ghosh et al. 2020, Zhang and Simon 2020, Hofer et al. 2022, Satarker et al. 2024). Importantly for our analysis, spermidine is yet another activator of Nrf2 (e.g., (Liu et al. 2019, Guo et al. 2022, Aihara et al. 2023, Niu et al. 2023, Imazu et al. 2024))
It is also of considerable interest, therefore, that spermidine improves placental angiogenesis and reproductive performance in pigs (Duan et al. 2025). This said, there seems to be very little other literature bearing on relationships between spermidine and pre-eclampsia (He et al. 2015, Shan et al. 2023), although they do seem to differ with foetal gender (Gong et al. 2018).

7. Ergothioneine and Cardiovascular Diseases

Ergothioneine (Figure 4) is an antioxidant thiohistidine derivative that exists as a tautomer, mostly as the form on the left of Figure 4, which importantly (Fahey 2013) makes it significantly resistant to autoxidation. It is also very heat stable (Alamgir et al. 2015). It is not synthesised by humans (who have instead selected nutrient transporters to take it up (Gründemann et al. 2005, Gründemann 2012, Yee et al. 2020, Gründemann et al. 2022)). However, it is widely available in the diet (Tian et al. 2023b), the main source being more or less any kind of culinary mushroom (Dubost et al. 2005, Martin 2010, Ito et al. 2011, Kalaras et al. 2017, Borodina et al. 2020, Tian et al. 2023b).
The useful bioactivities of ergothioneine have been widely reviewed (e.g., (Paul and Snyder 2010, Cheah and Halliwell 2012, Ames 2018, Halliwell et al. 2018, Borodina et al. 2020, Cordell and Lamahewage 2022, Halliwell et al. 2023, Tian et al. 2023b)). Its concentration has been associated positively with protection against endothelialitis (Li et al. 2014, D’Onofrio et al. 2016, Koh et al. 2021), and against a variety of cardiovascular diseases (e.g., (Smith et al. 2020)). There is also a very striking inverse relationship between the extent of mushroom consumption and the likelihood of suffering Mild Cognitive Impairment (Feng et al. 2019), something seen as being on the pathway to Alzheimer’s dementia.
Some time ago, we suggested (Kerley et al. 2018) that ergothioneine might have utility in delaying or preventing the development of pre-eclampsia, and this was indeed demonstrated in the rat RUPP model of pre-eclampsia (Williamson et al. 2020). In particular, we also showed (Kenny et al. 2023), based on data from the European part of the SCOPE study (Kenny et al. 2020), that women in the top ten percentiles for plasma ergothioneine concentration had an essentially negligible likelihood of developing either early or late pre-eclampsia. Some of those open access data are redrawn in Figure 5. While these data are extremely striking (Ho 2023) (in our view persuasively so) they were obtained from participants whose ergothioneine consumption was not controlled by the researchers in any way. Given the established pharmacokinetics (Cheah et al. 2017, Yau et al. 2024), the next step is to vary ergothioneine as an independent variable in a randomised control trial. However, for present purposes, the important point is that – while it is itself an antioxidant – one of the chief mechanisms of action of ergothioneine is that it stimulates Nrf2 (Hseu et al. 2015, Hseu et al. 2020, Kushairi et al. 2020, Zalachoras et al. 2020, Dare et al. 2021, Ko et al. 2021, Salama et al. 2021, Bernardo et al. 2022, Brancaccio et al. 2022, Dare et al. 2022, Fovet et al. 2022, Jeong et al. 2023, Jomova et al. 2023, Leow et al. 2023, Roda et al. 2023, Tian et al. 2023b) and hence an array of ARE-containing genes including antioxidant and xenobiotic detoxification enzymes, xenobiotic transporters and other metabolic enzymes including those involved in iron and lipid metabolism
Ergothioneine was found to be depleted in all-senescence-like phenotypes (Berardi et al. 2022), as well as in the elderly (Sotgia et al. 2014), and especially those exhibiting frailty (Kameda et al. 2020), and in those suffering poor outcomes from acute SARS-CoV-2 infection (Wu et al. 2020, Roberts et al. 2022). Furthermore, importantly for our hypothesis, ergothioneine treatment attenuated oxidative damage-induced senescence of mouse hippocampal neurons following tert-Butyl hydroperoxide exposure (Apparoo et al. 2024). Additionally, ergothioneine slowed telomere shortening during longitudinal culture of primary human fibroblasts in normal and oxidising conditions (Samuel et al. 2022). Taken together, these data suggest that ergothioneine may be senotherapeutic, and probably senomorphics, though the precise effects of ergothioneine on pathological placental oxidative damage and senescence remain to be evaluated. We also recognise that because of the role of senescence in normal placental development some senotherapeutics, especially senolytics, may be contra-indicated.

8. Use of Traditional Chinese Medicine in Modulating Autophagy

It is important to recognise that even individual small molecules are likely to bind to multiple targets; Mestres and colleagues in 2008 (Mestres et al. 2009) found an average of six known ones for marketed pharmaceutical drugs. In addition to the established small molecules mentioned above, a rather underexplored area of science is the use of the herbal formulae and other methods as proposed in Traditional Chinese Medicine (TCM) and in related equivalents such as the Japanese Kampo or Traditional Korean Medicine. Such cocktails are commonly rich in terpenoids and polyphenols. We have found the TCM concept of ‘blood stasis’ (Li et al. 2015, Liu et al. 2015, Choi et al. 2016, Zhang et al. 2017, Hireche-Chikaoui et al. 2018, Huang et al. 2021a, Huang et al. 2021b, Xin et al. 2021, Yu et al. 2022, Luo et al. 2023, Park et al. 2023, Fan et al. 2024, Yang et al. 2024a) of considerable value in understanding Long COVID (Kell et al. 2025), and given the similarities exhibited by both Long COVID and pre-eclampsia (Jayaram et al. 2021) it was of significant interest to see what evidence there is that TCM formulae might be capable of modulating autophagy. To this end, Table 3 summarises these.
It may be concluded from Table 3 that a considerable literature suggests that such natural products, additional to ergothioneine and others mentioned above, might thus also be of value in modulating autophagy and thus the incidence or severity of pre-eclampsia.

9. Concluding Remarks

Systems medicine seeks to establish the main pathways by which physiological processes occur, and how they may be reverted in the case of pathological states. It is now well established that both early and later pre-eclampsia involve oxidative stress. In the present case, therefore, we have brought together ideas and evidence linking placental senescence, senotherapeutics and autophagy, with a focus on small molecules and cocktails that might affect these processes, in particular via Nrf2 and the ARE-containing genes that it controls. The next steps clearly involve some kind of trials of these molecules. ‘Coherence’ describes a Philosophy of Science concept by which if multiple, orthogonal lines of evidence lead to the same conclusion that conclusion is thereby strengthened (Thagard 1989, Thagard 1998, Thagard 1999, Thagard 2007, Thagard 2008, Thagard 2012). We consider that in this sense these elements paint a self-consistent and coherent picture.

Author Contributions

All authors contributed to the conceptualisation, analyses, funding acquisition, drafting, and final editing. All authors have read and agreed to the published version of the manuscript.

Funding

D.B.K. thanks the Balvi Foundation (grant 18) and the Novo Nordisk Foundation for funding (grant NNF20CC0035580). E.P.: Funding was provided by NRF of South Africa (grant number 142142) and SA MRC (self-initiated research (SIR) grant), and Balvi Foundation. The content and findings reported and illustrated are the sole deduction, view and responsibility of the researchers and do not reflect the official position and sentiments of the funders.

Acknowledgments

We thank Massimo Nunes for drawing our attention to the role of senescence in the context of Long COVID.

Conflicts of Interest

E.P. is a named inventor on a patent application covering the use of fluorescence methods for microclot detection in Long COVID. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Figure 1. An overview of cellular senescence. Taken from the CC-BY 4.0 Open Access publication (Yang et al. 2021).
Figure 1. An overview of cellular senescence. Taken from the CC-BY 4.0 Open Access publication (Yang et al. 2021).
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Figure 2. A systems biology overview of what we see as elements of the most important steps in the development of early- and late-term pre-eclampsia, as per the modern version (Redman et al. 2014, Redman and Staff 2015, Staff 2019, Redman et al. 2022) of the two-stage model, and the role of small molecules in stopping this by inducing Nrf2 activity. Based in part on Figure 1 of (Sugulle et al. 2024).
Figure 2. A systems biology overview of what we see as elements of the most important steps in the development of early- and late-term pre-eclampsia, as per the modern version (Redman et al. 2014, Redman and Staff 2015, Staff 2019, Redman et al. 2022) of the two-stage model, and the role of small molecules in stopping this by inducing Nrf2 activity. Based in part on Figure 1 of (Sugulle et al. 2024).
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Figure 3. Essential mechanisms of modulation of the Keap1/Nrf2 pathway. (A) The mechanism of Keap1/Nrf2−ARE pathway activation. Under basal conditions, cytoplasmic Nrf2 is inhibited by Keap1 binding, and may be targeted by the Cul3-Rbx1 ubiquitination system for proteasomal degradation. Under oxidative stress, Nrf2 is released from Keap1 for phosphorylation of Nrf2 or Keap1 modification, enters the nucleus, and subsequently acts as a transcription factor to activate Nrf2 pathways. (B) The Keap1-dependent Nrf2−ARE pathway. There are three accepted mechanisms on Keap1-dependent Nrf2−ARE pathway activation, which including (1) Keap1 dissociation: Keap1 cysteine modifications of various types may cause the release of Nrf2 from Keap1 in the cytoplasm; (2) Keap1 hinge and latch: Keap1 cysteine modification may cause a conformational change, which likely disrupts the weak latch binding site to prevent ubiquitin conjugation onto Nrf2; (3) Keap1 ubiquitination: Keap1 cysteine modification may stop ubiquitin binding to Nrf2. All of the above three pathways finally cause Nrf2 translocation to the nucleus so as to activate ARE. (Taken in toto from the Open Access CC-BY publication (Qin and Hou 2016)).
Figure 3. Essential mechanisms of modulation of the Keap1/Nrf2 pathway. (A) The mechanism of Keap1/Nrf2−ARE pathway activation. Under basal conditions, cytoplasmic Nrf2 is inhibited by Keap1 binding, and may be targeted by the Cul3-Rbx1 ubiquitination system for proteasomal degradation. Under oxidative stress, Nrf2 is released from Keap1 for phosphorylation of Nrf2 or Keap1 modification, enters the nucleus, and subsequently acts as a transcription factor to activate Nrf2 pathways. (B) The Keap1-dependent Nrf2−ARE pathway. There are three accepted mechanisms on Keap1-dependent Nrf2−ARE pathway activation, which including (1) Keap1 dissociation: Keap1 cysteine modifications of various types may cause the release of Nrf2 from Keap1 in the cytoplasm; (2) Keap1 hinge and latch: Keap1 cysteine modification may cause a conformational change, which likely disrupts the weak latch binding site to prevent ubiquitin conjugation onto Nrf2; (3) Keap1 ubiquitination: Keap1 cysteine modification may stop ubiquitin binding to Nrf2. All of the above three pathways finally cause Nrf2 translocation to the nucleus so as to activate ARE. (Taken in toto from the Open Access CC-BY publication (Qin and Hou 2016)).
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Figure 4. The tautomeric structure of ergothioneine.
Figure 4. The tautomeric structure of ergothioneine.
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Figure 5. Relationship between the likelihood of developing term (late) or preterm (early) pre-eclampsia and plasma ergothioneine concentration. Data are taken and redrawn from the supplementary information in (Kenny et al. 2023), where the numbers are term PE 74 individuals, pre-term PE 23 individuals, no PE 335 individuals, total 432. The dotted vertical line represents the 90th percentile of ergothioneine concentration (462 ng/mL) while the full vertical line represents 500 ng/mL. No individual suffered from pre-eclampsia if their plasma ergothioneine concentration exceeded the latter value. Data have been jittered vertically to improve clarity.
Figure 5. Relationship between the likelihood of developing term (late) or preterm (early) pre-eclampsia and plasma ergothioneine concentration. Data are taken and redrawn from the supplementary information in (Kenny et al. 2023), where the numbers are term PE 74 individuals, pre-term PE 23 individuals, no PE 335 individuals, total 432. The dotted vertical line represents the 90th percentile of ergothioneine concentration (462 ng/mL) while the full vertical line represents 500 ng/mL. No individual suffered from pre-eclampsia if their plasma ergothioneine concentration exceeded the latter value. Data have been jittered vertically to improve clarity.
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Table 1. Some biomarkers of cellular senescence seen in the development of pre-eclampsia and related disorders of pregnancy.
Table 1. Some biomarkers of cellular senescence seen in the development of pre-eclampsia and related disorders of pregnancy.
Selected references Senescence Biomarkers and proposals Comments
(Barak et al. 2025) Multiple, including FSTL3, VEGFA, and DKK1 Measured via placental transcripts
(Chen et al. 2021b) Reduced a-Klotho expression and increased levels of p21, p53, p16, and SAβG activity in advanced maternal age compared to placentas from young control donors Maternal age leads to senescence and PE
(Cindrova-Davies et al. 2018) PE placentas exhibited increased p21 and γH2AX levels compared to healthy control placentas. Evidence of oxidative stress-induced senescence
(Cox and Redman 2017) Review of multiple biomarkers including excessive telomere attrition in PE trophoblasts Senescence also occurs in normal pregnancy development
(Davy et al. 2009) Telomere shortening and increased p16 and p21 transcripts in foetal growth restriction placentas Correlates with foetal growth restriction
(Farladansky-Gershnabel et al. 2019) Decreased telomere length and increased levels of p16 transcripts and SAβG activity in PE compared to gestational age-matched healthy controls, particularly in early-onset PE Telomere homeostasis worse in PE, more so in early onset PE
(Fox 1967) Regressed villi seen as reflecting senescence Early detection of senescence in placental villi
(Hu et al. 2022) Nitro-L-arginine methyl ester-induced PE mouse model exhibited increased placental p53 and p21 levels; attenuated by cyclosporin A through induction of autophagy Cyclosporin A relieves trophoblast apoptosis and senescence in mouse model of PE
(Hu et al. 2023) Pregnant Rat Model
of Polycystic Ovary Syndrome shows increased placental senescence (phospho-p53, p21, and γH2AX)		 Uses a Pregnant Rat Model
of Polycystic Ovary Syndrome
(Huang et al. 2022) Activation of Nrf2 by human placental extract helps delay replicative and oxidative stress-induced senescence in cultured human dermal fibroblasts
(Kajdy et al. 2021) Review of placental ageing (that may be considered to relate to senescence) Includes foetal growth restriction and stillbirth
(Lee et al. 2022) Decreased caveolin-1 and increased p53/p21, particularly in early compared to late-onset PE placentas Senescence markers in PE
(Manna et al. 2019) Review of multiple markers of aberrant senescence in adverse pregnancy outcomes Relation to PE
(Negre-Salvayre et al. 2022) Review, lipid oxidation products such as 4-hydroxy-2-nonenal present in severe PE and may drive oxidative stress-induced placental senescence Stimulation of senescence
(Peng et al. 2025) Various, including apelin and apoptotic markers Apelin increases oxidative stress and senescence in PE
(Roh et al. 2024) Increased SASP molecules in human PE serum and placenta, and PE placental SAβG+ and p21+ cells. Senolytic treatment with fisetin improved cardiac function in mouse model of peripartum cardiomyopathy Assessed using serum proteomics
(Scaife et al. 2021) Increased expression of p21 and levels of NOX4 and 8-OHdG (indicative of oxidative DNA damage) in PE compared to term normotensive placentae. Gestational age associated with increased placental p16 expression Senescence biomarkers parallel oxidative stress
(Siddique and Cox 2022) Gene expression analysis of placentas across several subtypes of PE show accelerated senescence Increased downregulation of anti-senescence gene expression, e.g., CDK2
(Sugulle et al. 2024) Review of senescence and PE Multiple senescence biomarkers summarised
(Sultana et al. 2018) Review of senescence in pregnancy disorders
(Suvakov et al. 2019) Increased senescence (SAβG activity, and IL-6, IL-6, MCP-1, PAI-1, PA-2, p16, p21 mRNA expression) in mesenchymal stem cells from PE compared to normal pregnancies. Senolytic treatment of PE MSCs improved angiogenic potential Inhibit angiogenesis in PE
(Suvakov et al. 2023) Comprehensive review
(Suvakov et al. 2024) Multiple ageing markers Related to those seen n PE and senescence
(Tao et al. 2023) Increased senescence (high p53/p21, γH2AX and d-OHdG levels, and SAβG activity, low CDK2) in placentas from obese compared to non-obese pregnancies. Adipocyte-derived exosomes from obese donors contain NOX4; exposure of human trophoblasts to NOX4+ exosomes from obese human adipocytes induced senescence through oxidative damage NOX4-mediated oxidative damage induces premature placental senescence in obese pregnancy
(Tasta et al. 2021) Increased γH2AX+ DNA damaged cells with lipofuscin granules in PE compared to normal placentas. Induced by oxidative stress marker 4-hydroxy-2-nonenal Induced by oxidative stress marker 4-hydroxy-2-nonenal
(Wang et al. 2022) Multiple biomarkers (p21, p53, p16, pRb, SAβG activity) increased in PE compared to normal placentas; decrease in SIRT expression. SIRT1 activation by resveratrol decreases senescence in forskolin-activated cells SIRT1 activation by resveratrol decreases senescence in forskolin-activated cells
(Zhang et al. 2024b) Single cell sequencing shows exacerbation of senescence in placental mesenchymal stem/stromal cells from PE compared to healthy donors Single cell sequencing shows senescence in PE
(Zhong et al. 2022) Increased senescence (p16, p53, SAβG activity, decreased S-phase proliferation) in placental mesenchymal stem cells isolated from PE compared to healthy placentas. Related to increased TLR4 expression and decreased Hedgehog signalling. Suppression via LPS acting of TLR4 causing senescence as judged e.g., by SAβG activity Suppression via LPS acting of TLR4 causing senescence as judged e.g., by SASP
(Zhu et al. 2022) Gestational exposure to NO2 in mice drives reduced Sirt1 and Tert expression, leading to short telomeres and senescence Gestational exposure to NO2 aggravates senescence
Table 2. Some literature detailing the involvement of Nrf2 in the development, delay, or prevention of pre-eclampsia.
Table 2. Some literature detailing the involvement of Nrf2 in the development, delay, or prevention of pre-eclampsia.
Literature references Comments
(Chapple et al. 2015) Review of the role of Nrf2-Keap1 in foetal protection in utero
(Chigusa et al. 2012) Low placental Nrf2 activation in pre-eclampsia
(He et al. 2023) Metformin is protective against pre-eclampsia by various mechanisms, including Nrf2 activation
(Ju et al. 2022) A combined treatment of rats with apocyanin and aspirin activates the PI3K/Nrf2/HO-1 signaling pathway and is protective against pre-eclampsia
(Khadir et al. 2022) Polymorphisms in the Nrf2 gene modulate the risk of pre-eclampsia
(Kweider et al. 2011, Kweider et al. 2012) Interplay between VEGF and Nrf2 affects/ regulates pre-eclampsia
(Kweider et al. 2013, Kweider et al. 2014) Role of the Nrf2/HO-1 pathway in preventing PE
(Li et al. 2020) Here simultaneous downregulation of placental Nrf2 and sFlt1 improved maternal and fetal outcomes in a pre-eclampsia mouse model
(Liao et al. 2022) Upregulating the Nrf2/GPX4 signalling pathway inhibits trophoblast ferroptosis and alleviates pre-eclampsia
(Liu et al. 2022b) Use of procyanidin B2 to ameliorate dysfunction of endothelia and angiogenesis via Nrf2/PPARγ/sFlt-1 in pre-eclampsia
(Liu et al. 2025b) Vitamin D3-driven foetal protection vs pre-eclampsia via Nrf2
(Mundal et al. 2022) Differences in Nrf2 between pre-eclampsia with and without Foetal Growth Restriction
(Muralimanoharan et al. 2018) NRF2 promotes syncytiotrophoblast
differentiation and is dysregulated in preeclampsia.
(Nezu et al. 2017) Nrf2 inactivation enhances placental angiogenesis in a RAS-based mouse model of pre-eclampsia
(Padron et al. 2022) Downregulation of Nrf2 in Primary Amnion Cells caused by stretch, and alleviation via Nrf2 stimulation
(Tantengco et al. 2021a) Review of the role of Nrf2 in the pathophysiology of preeclampsia
(Tossetta et al. 2023) Review, also discussing natural and synthetic compounds that can regulate he Nrf2/Keap1 pathway
(Wang et al. 2021a) Inhibition of ERK/Nrf2 signalling pathway by lowering CD151 (a tetraspanin) induces oxidative stress in trophoblast cells in pre-eclampsia
(Xu et al. 2024) Epigallocatechin gallate alleviates inflammation, endothelial dysfunction and placental ferroptosis, and improves pregnancy outcomes in PE-like rats via eNOS/Nrf2/HO-1
(Yanagisawa et al. 2023) Oxidative stress in preeclamptic placentae may activate the trophoblast ATX–LPA system via the Nrf2 pathway to effect protection
(Yang et al. 2020) Astragaloside IV, a Traditional Chinese Medicine (TCM) component, ameliorates oxidative stress and pre-eclampsia via the Nrf2/HO-1 pathway in a rat model
(Yu et al. 2019) The protective role of Nrf2 in PE is partially mediated via ATP-binding cassette transporters
(Zakeri et al. 2024) Decreased expression of the Nrf2 gene in PE is mediated in part via epigenetic gene methylation
Table 3. Some literature detailing the use of Traditional Chinese Medicine for modulating autophagy.
Table 3. Some literature detailing the use of Traditional Chinese Medicine for modulating autophagy.
Literature Reference Comments
(Chen et al. 2020) Focus on role of TCM in Alzheimer’s Disease including reduction of b-amyloid via autophagy
(Chen et al. 2021a) Attenuation of lipidosis in oxidised-LDL-stimulated macrophages by stimulating Beclin-1-induced autophagy
(Cui and Yu 2018) Useful review of the use of TCM, especially natural products (Chuang et al. 2014), in autophagy
(Gao et al. 2019) Inhibition of liver cancer growth via induction of autophagy and cell cycle arrest
(Han et al. 2023) Role of autophagy, especially as stimulated by flavonoids, in ameliorating alcoholic liver disease
(He et al. 2025) Acupuncture can modulate autophagy via LC3, Beclin1, p53, and autophagy-associated (ATG) protein expression.
(Huang et al. 2015) Neuronal protection by autophagy in cerebral ischaemia, as stimulated by various TCM herbs
(Liu et al. 2017) TCM herbal extracts inducing autophagy for treating nonalcoholic fatty liver disease
(Liu et al. 2022c) Inhibition of colorectal cancer cell proliferation via autophagy induction
(Liu et al. 2024b) Use of various active ingredients from TCM that modulate autophagy to reduce liver fibrosis
(Shi et al. 2022) Use of various active ingredients from TCM that modulate autophagy for ameliorating glomerular diseases
(Tao et al. 2022) Use of various active ingredients from TCM that modulate autophagy for ameliorating dementia
(Tian et al. 2023a) Use of various active ingredients from TCM that modulate autophagy for ameliorating Systemic lupus erythematosus (‘Lupus’)
(Wang et al. 2015) Use of various active ingredients from TCM that modulate autophagy for ameliorating myocardial ischaemia
(Wang et al. 2016) Use of various active ingredients from TCM that modulate autophagy for ameliorating cancer and neurodegenerative diseases
(Wang et al. 2020, Wang et al. 2024a) Role of Yishen Huazhuo decoction in reducing Alzheimer’s disease-related neuroinflammation and lowering Ab1-42
(Wang et al. 2021b) Role of TCM compounds in regulating autophagy for treating neurodegenerative diseases
(Wei et al. 2015) Describes a formula for preventing autophagy in experimental stroke
(Wu et al. 2018a, Wu et al. 2018b) TCM-induced cell growth inhibition, autophagy and apoptosis in prostate cancer via the EGFR pathway
(Wu et al. 2025) The use of qili qiangxin capsule protects against myocardial ischemia-reperfusion injury via the suppression of autophagy
(Zhao et al. 2023) Bibliometric analysis of 916 papers reporting on TCM and autophagy
 
(Zhu et al. 2017) Focuses on Ka-Sai-Ping, a TCM formula that suppresses the growth of gastric cancers via induction of autophagy
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