Autophagy is a highly conserved intracellular quality-control system in which cytoplasmic material is sequestered into double-membrane vesicles called autophagosomes and delivered to lysosomes for degradation and recycling. The process is orchestrated by autophagy-related gene products, with initiation controlled by the ULK1 kinase complex and regulated on one side by the nutrient-sensing kinase mTOR, which suppresses autophagy when resources are abundant, and on the other by AMP-activated protein kinase, which activates it under energy stress. Beyond bulk recycling, selective forms of autophagy use cargo receptors such as p62/SQSTM1 to remove damaged mitochondria, protein aggregates, and invading microbes. In tissues that undergo constant remodeling, including the endometrium, which regenerates and sheds every menstrual cycle, this housekeeping function is not a luxury but a structural requirement.

The review first lays out the general logic of autophagy-mediated fibrosis, drawing on studies of lung, liver, kidney, skin, and heart. Fibrosis is the pathological endpoint of chronic tissue injury: activated fibroblasts differentiate into contractile, collagen-secreting myofibroblasts marked by alpha-smooth muscle actin, and they deposit excessive extracellular matrix rich in collagen type I, collagen type III, and fibronectin. The master profibrotic cytokine is transforming growth factor beta, which drives fibroblast activation, epithelial-to-mesenchymal transition, and fibroblast-to-myofibroblast transition. When autophagy is impaired, damaged mitochondria accumulate, reactive oxygen species rise, and cells slip into senescence, a state of permanent growth arrest accompanied by a senescence-associated secretory phenotype that floods the tissue with inflammatory cytokines such as interleukin-6 and interleukin-8. This oxidative and inflammatory milieu reinforces TGF-beta signaling, creating what the literature describes as a perverse cycle in which TGF-beta and reactive oxygen species amplify one another.

Applied to the endometrium, this framework explains much of what goes wrong in the aging uterus. Evidence from intrauterine adhesions, also known as Asherman’s syndrome, shows that defective autophagy contributes to endometrial epithelial-mesenchymal transition, a process in which epithelial cells lose their identity and acquire motile, matrix-producing characteristics. Overactivated Sonic hedgehog signaling aggravates intrauterine adhesions by inhibiting autophagy in endometrial stromal cells, while reduced expression of the inhibitory SMAD7 diminishes autophagy and promotes the transition of stromal cells into myofibroblasts. Loss of the Wnt antagonist DKK1 promotes fibrosis through autophagy dysregulation and exosome-mediated macrophage-to-myofibroblast transition, showing that immune cells can be recruited into the scarring program. In each case, the failure of cellular quality control appears upstream of matrix accumulation and declining receptivity.

Decidualization, the transformation of endometrial stromal cells that makes the lining receptive to an embryo, adds another layer of vulnerability. Genetic work has shown that the autophagy gene Atg16L1 is necessary for normal decidualization in mice, and endometrial autophagy has been shown to be essential for embryo implantation in early pregnancy. Rapamycin, an mTOR inhibitor that pharmacologically induces autophagy, has been reported to prevent spontaneous abortion in mouse models by triggering autophagy in decidual stromal cells, which in turn influences the residence of uterine natural killer cells. Senescent decidual cells, which accumulate with age and impair implantation in human endometrial assembloid models, are normally cleared by uterine natural killer cells during the menstrual cycle, a surveillance system that itself depends on the plasticity of the tissue. When autophagic flux falters, senescent cells persist, the secretory phenotype spreads, and the delicate decidual microenvironment deteriorates.

Yet the review is emphatic that the story does not end with autophagy as a universal protector. Under specific cellular and microenvironmental conditions, autophagy can facilitate profibrotic remodeling. In hepatic stellate cells, autophagy liberates lipids that fuel the activated, collagen-producing state. In other fibrotic settings, autophagy fosters myofibroblast differentiation through mTORC2 activation and downstream upregulation of connective tissue growth factor, and TGF-beta itself can induce autophagy through epigenetic regulation involving the acetyltransferase MYST1, thereby potentiating fibrosis. Transcription factor EB, a master regulator of lysosomal biogenesis and autophagy, has been shown to promote dermal fibroblast differentiation and collagen production. Mechanosignaling through the YAP/TAZ pathway, which drives fibroblast activation in fibrotic organs, requires autophagic flux to sustain cell phenotypic plasticity. In aging trabecular meshwork cells of the eye, enhanced autophagy activity promotes fibrotic progression via TGF-beta signaling. The direction of the effect, protective or pathological, depends on which cell is autophagying, what it is degrading, and what signals surround it.

This duality has direct consequences for how researchers should interpret endometrial data. Kobayashi’s review explicitly distinguishes mechanisms established in the endometrium from concepts extrapolated from other organs, a caution that matters because the endometrium is unusual: it cycles, sheds, and regenerates, tolerates repeated inflammatory bursts during menstruation, and supports a uniquely immunologically complex interface with the embryo. A pathway that restrains fibrosis in the kidney might accelerate it in a stromal cell responding to TGF-beta, and the review argues that only cell type-specific and age-dependent studies can resolve which regime dominates in the human uterus at a given life stage.

The translational implications are considerable but tempered. If impaired autophagy drives endometrial senescence and scarring, then restoring autophagic flux could, in principle, rejuvenate the lining and improve receptivity in patients of advanced maternal age or those with intrauterine adhesions. Fibroblast growth factor 1 has been reported to ameliorate thin endometrium in rats through activation of the autophagic pathway, and natural products that enhance autophagy are being explored as aids to embryo implantation. But the dual-role problem cuts the other way: indiscriminate autophagy activation could nourish myofibroblast differentiation and worsen fibrosis in the wrong cellular context. Safe therapeutic strategies will therefore require biomarkers that reveal, in a given patient’s endometrium, whether autophagy is deficient, excessive, or misdirected, and at which cell type.

The review also situates endometrial aging within the broader hallmarks of aging. Autophagy declines with age across tissues, and its loss promotes mitochondrial dysfunction, oxidative stress, stem cell exhaustion, and cellular senescence, all recognized drivers of aging. Single-cell transcriptomic studies of endometrium from women of advanced maternal age reveal disturbed decidual microenvironments, accumulation of senescent and multiciliated epithelial cells, and altered signaling landscapes, consistent with a lining that has lost the plasticity associated with successful implantation. Evolutionary framing, including the concept of antagonistic pleiotropy, suggests that pathways beneficial in early reproductive life may become detrimental later, which could explain why a quality-control system as fundamental as autophagy is not simply maximized throughout life.

What emerges is a research agenda rather than a finished therapy. Priority questions include mapping autophagic flux in specific endometrial cell populations across the reproductive lifespan, defining the tipping points at which autophagy switches from antifibrotic to profibrotic, and validating whether markers such as LC3-II, p62/SQSTM1, and Beclin-related activity can serve as clinically useful readouts of endometrial health. The review’s careful separation of endometrium-specific evidence from organ-external extrapolation is itself a methodological contribution, urging the field to test, rather than assume, that lessons from liver and lung apply to the womb. For millions of people pursuing pregnancy at older ages, understanding when to boost and when to restrain this cellular recycling program may prove decisive for keeping the aging endometrium receptive.

Subject of Research: The dual, context-dependent roles of autophagy in endometrial fibrosis and age-related reproductive dysfunction

Article Title: Dual Roles of Autophagy in Endometrial Fibrosis and Its Implications in Age-Related Reproductive Dysfunction

Article References: Kobayashi, H. (2026). Dual Roles of Autophagy in Endometrial Fibrosis and Its Implications in Age-Related Reproductive Dysfunction. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02192-7

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02192-7

Keywords: autophagy, endometrium, fibrosis, reproductive aging, endometrial receptivity, cellular senescence, TGF-beta, decidualization, intrauterine adhesions, mitochondrial dysfunction, epithelial-mesenchymal transition, fertility

The stakes could hardly be higher. The endometrium sits at the centre of embryo implantation, pregnancy maintenance and broader reproductive and systemic health, yet conditions affecting it—endometriosis, adenomyosis, recurrent implantation failure, recurrent pregnancy loss and chronic endometritis—remain poorly understood and notoriously difficult to treat. The authors argue that the root of this knowledge gap lies in the tools the field has historically depended upon: animal models and two-dimensional cultures that systematically fail to reproduce the human endometrium’s intrinsic biology.

The problem with animal models begins with basic evolutionary divergence. Mice, the workhorse of biomedical research, do not menstruate, and their endometrial architecture, hormone responsiveness and decidualization programmes—divided into the stem-cell-rich basalis that regenerates the tissue each cycle and the functionally active functionalis that is shed during menstruation—differ in fundamental ways from those of humans. Even the spiny mouse, the only rodent known to menstruate, offers only a partial bridge. Baboons show spontaneous endometriosis, making them useful but expensive and ethically constrained. The review details how comparative studies between human and rat endometrial co-cultures have repeatedly exposed these species-specific gaps, underscoring why findings from mice frequently fail to translate into human clinical practice.

Two-dimensional cell culture, meanwhile, has its own structural limitations. Landmark studies dating back to the early twentieth century established the foundations of tissue culture, and endometrial research made enormous strides with immortalized cell lines such as Ishikawa and HEC-1 adenocarcinoma-derived cells, alongside primary cultures of endometrial epithelial glands and stromal cells isolated as early as the 1970s. These systems enabled researchers to dissect steroid metabolism, integrin expression, 17 beta-hydroxysteroid dehydrogenase regulation and paracrine signalling between epithelium and stroma. Yet flat monolayers strip away the three-dimensional geometry, cell polarity, extracellular matrix interactions and multicellular composition that define how the endometrium actually behaves—particularly during the precisely timed window of implantation, when epithelial polarity shifts and stromal cells undergo decidualization under progesterone control.

The inflection point arrived in 2017, when two independent teams grew long-term, hormone-responsive organoids from human endometrium in chemically defined media. These miniature, self-organizing structures, built from endometrial epithelial stem and progenitor cells, recapitulated key features of endometrial physiology, expanded over successive passages and responded to oestrogen and progesterone much as the native tissue does. Suddenly, researchers could grow living endometrial epithelium indefinitely, derive it from patients with disease, and interrogate its biology with genetic and pharmacological tools. Follow-up work showed that patient-derived organoids could capture clinical heterogeneity in endometrial disease and were amenable to drug screening—opening a genuine pathway toward personalized medicine in gynaecology.

The next generation of models has pushed further toward physiological realism. Multi-lineage assembloids now combine endometrial epithelium with stromal fibroblasts, immune components, endothelial cells and extracellular matrix in engineered assemblies that mimic the tissue’s natural architecture. Recent protocols for generating mouse and human endometrial assembloids allow epithelial–stromal crosstalk to be studied within a single three-dimensional construct, while air–liquid interface methods have yielded assembloids possessing a luminal epithelium—the very surface a blastocyst must breach during implantation. Studies using assembloids have already modelled how decidual senescence impairs embryo implantation and how adenomyosis-related endometrial receptivity is compromised, delivering mechanistic insights that flat cultures simply could not provide.

Bioengineering has multiplied these capabilities. Microfluidic endometrium-on-a-chip devices compartmentalize perivascular stroma and endothelial cells to create vascularized tissue architectures, and experiments within them have shown that hemodynamic forces enhance decidualization via endothelial-derived prostaglandin E2 and prostacyclin—demonstrating that mechanical cues from blood flow, absent in static cultures, are genuine regulators of endometrial function. Fully synthetic hydrogels have replaced animal-derived Matrigel in several systems, enabling precise control of matrix composition and permitting organoid co-cultures of epithelium and stroma to be studied in defined extracellular environments. Bioprinted, hormone-responsive bilayer models now reproduce the tissue’s layered structure, and engineered platforms incorporating a 28-day hormonal cycle have simulated the human menstrual cycle in vitro, capturing epithelial cell transitions during menstruation and regeneration.

Perhaps the most consequential frontier is implantation itself. Because direct observation of human embryo implantation is ethically impossible, the field has had to infer its mechanics from indirect evidence. That barrier is now falling. Stem-cell-derived blastoids and trophoblast organoids can be co-cultured with engineered endometrial models to recreate the first contact between embryo and maternal tissue. Recent studies have modelled the embryo–endometrial interface in three dimensions, produced human receptive endometrial assembloids designed to decode the implantation window, and developed microfluidic platforms that measure embryo adhesion in real time. The review highlights 2026 studies reporting three-dimensional post-implantation co-culture of human embryo and endometrium models, alongside paired investigations of implantation and implantation failure—work that together promises to reveal the molecular dialogue between embryo and mother at unprecedented resolution. Single-cell atlases of the endometrium and the maternal–fetal interface, including a recently published spatiotemporal dissection of the human maternal–fetal interface, are providing the reference maps against which these engineered systems can be validated.

The clinical implications radiate across women’s health. Endometriosis, a chronic systemic disease affecting an estimated one in ten women of reproductive age, has seen its cellular basis illuminated by single-cell transcriptomic studies of eutopic and ectopic tissue, multi-ancestry genome-wide association analyses and investigations of microRNA signatures in tissue, serum and extracellular vesicles—several of which show promise as non-invasive diagnostic biomarkers. Patient-derived organoids from endometriosis lesions and early peritoneal endometriosis models now allow drug testing on a patient’s own disease cells. Endometrium-on-chip platforms built from patient cells are being evaluated for assessing endometrial receptivity and guiding personalized fertility treatment, while recent organoid work has even traced the donor-derived cellular origin of endometrium after uterus transplantation. Insulin- and glucose-induced alterations in endometrial transcriptomes observed on-chip hint at mechanisms linking metabolic health to fertility, and scaffold-free organoids have been shown to respond to the excess androgens characteristic of polycystic ovarian syndrome.

The authors are candid that substantial challenges remain. Matrigel, the tumor-derived basement membrane matrix underpinning many organoid protocols, is chemically undefined and variable, motivating ongoing efforts to develop fully synthetic alternatives. Vascularization, immune cell incorporation and the biophysical environment of the uterus—contractions, blood flow, cyclic mechanical remodeling—are only partially captured by existing systems. Ethical governance is advancing alongside the science: revised international stem cell guidelines now specifically address stem-cell-based embryo models, and frameworks for embedded ethics and dynamic consent are being proposed for research that grows ever closer to reconstructing human development in a dish. Competition-of-interest disclosures and peer oversight remain part of the field’s infrastructure as its translational potential grows.

What emerges from this sweeping synthesis is a portrait of a field in the midst of a genuine paradigm shift. By uniting developmental biology, stem-cell science, tissue engineering and single-cell genomics, researchers are converging on engineered endometria that are hormone-responsive, multicellular, vascularized and patient-specific. Such systems could transform how infertility is diagnosed, how endometriosis is treated and how the safety of new therapeutics is tested—without recourse to animal models that so often mislead. More profoundly, they are rewriting what it means to understand human reproduction: replacing inference from mice with direct observation in human-like tissue, and giving clinicians, for the first time, a living laboratory in which the earliest events of human life can be watched, perturbed and, ultimately, protected.

Beyond implantation, the cyclical nature of the endometrium itself presents a modelling challenge that these new platforms are beginning to address. Unlike most human tissues, the endometrium undergoes scarless repair after each menstrual shedding, a process driven by adult stem and progenitor cells residing in the basalis. Organoid systems that sustain long-term expansion now allow this regenerative capacity to be examined directly, complementing single-cell reference atlases that have catalogued the tissue’s cellular diversity across the menstrual cycle.

The immune dimension is equally critical. Uterine natural killer cells and other maternal immune populations orchestrate fetal–maternal tolerance and guide the differentiation of invading trophoblast, yet most current models lack immune components entirely. Integrating these lineages into assembloids and chip platforms remains an active area of development, informed by single-cell reconstructions of the maternal–fetal interface.

For patients, the promise is tangible: organoids derived from diseased tissue preserve the molecular signatures of the individual they came from, enabling drug responses to be tested outside the body. As these models mature, they may reduce reliance on both animal experimentation and empirical trial-and-error in fertility clinics, offering a mechanistic bridge between a patient’s cellular biology and her clinical care.

Subject of Research: Bioengineered three-dimensional models of the human endometrium, including organoids, assembloids and microfluidic devices, for studying implantation, endometrial disease and personalized reproductive medicine.

Article Title: Engineering the human endometrium at the intersection of development and reproduction

Article References: Vélez-Avilés, A. N., Abel, A., Taylor, H. S., & Sozen, B. (2026). Engineering the human endometrium at the intersection of development and reproduction. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-026-01789-2

Image Credits: AI Generated

DOI: 10.1038/s41551-026-01789-2

Keywords: human endometrium, organoids, assembloids, endometrium-on-a-chip, embryo implantation, endometriosis, tissue engineering, decidualization, stem cells, women's health, single-cell transcriptomics, personalized medicine