Autophagy’s Double-Edged Role in Womb Scarring and Age-Related Fertility Decline

As more people delay childbearing into their late thirties and forties, the biology of the aging uterus has moved from a niche interest to a central clinical question. A new review published in Reproductive Sciences by Hiroshi Kobayashi of Nara Medical University synthesizes a decade of evidence on autophagy, the cell’s ancient self-cleaning machinery, and its surprisingly contradictory role in endometrial fibrosis, the scarring and stiffening of the uterine lining that undermines implantation and pregnancy success in older patients. The review’s central message is that autophagy is neither simply protective nor simply harmful: depending on the cell type, the microenvironment, and the stage of disease, the same pathway can either hold fibrosis at bay or actively fuel it.

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