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

Incretins occupy a central position in the entero-insular axis, the signalling network by which the gut primes the pancreas to release insulin after a meal in a glucose-dependent manner. GLP-1, a 30-amino-acid polypeptide secreted by L cells of the terminal ileum and colon, binds a G protein-coupled receptor distributed across pancreatic islets, adipose tissue, the cardiovascular system, the central nervous system and, crucially, the reproductive organs. Its classical action involves activation of the cAMP/PKA cascade in pancreatic beta cells, enhancing insulin gene transcription and glucose-dependent insulin secretion. The hormone also regulates voltage-dependent calcium channels to promote calcium influx, suppresses glucagon release from alpha cells, and engages the PI3K pathway to sharpen peripheral insulin sensitivity.

The molecular picture has grown considerably richer in recent years. Researchers identified the adipokine zinc-alpha2-glycoprotein as a possible mediator of the metabolic benefits of GLP-1 receptor agonists, with twelve weeks of liraglutide treatment significantly elevating circulating ZAG levels in patients with type 2 diabetes. Other teams have explored ways to boost the body’s own GLP-1 output: the dietary compound imperatorin and glycyrrhizic acid, a principal component of licorice, both activate the TGR5 receptor to enhance GLP-1 secretion in experimental models. Even receptor architecture is proving malleable—bioluminescence resonance energy transfer studies revealed that the GLP-1 receptor can form heterodimers with the secretin receptor in islet cells, altering calcium signalling and inducing cross-desensitisation between the two receptors.

GIP, the second major incretin, is a 42-amino-acid peptide produced by K cells in the duodenum and jejunum. Though less intensively studied than GLP-1, it promotes insulin biosynthesis, supports beta-cell differentiation and survival, and enhances fat storage and bone formation. Work by Samms and colleagues showed that GIP enhances lipoprotein lipase activity in adipocytes through a PI3K/PKB-LKB1/AMPK-TORC2 signalling axis, promoting lipid uptake and storage while increasing insulin sensitivity. Intriguingly, GIP and GLP-1 signalling appear intertwined: N-glycosylation-deficient GIP receptors can be functionally rescued by co-expression with wild-type GLP-1 receptors, hinting at functional heterodimerisation between the two receptor classes.

The most clinically mature application in gynaecology is polycystic ovary syndrome, a condition characterised by hyperandrogenemia and insulin resistance that affects a growing number of women worldwide. Studies have confirmed abnormal secretion of both GIP and GLP-1 in patients with PCOS, and clinical research has shown that GLP-1 receptor agonists such as liraglutide and semaglutide can improve menstrual regularity, raise ovulation rates and reduce body fat. Mechanistically, the agonist exenatide was found to improve insulin resistance in PCOS rats by activating the AMPKalpha-SIRT1 pathway, while GLP-1 receptor agonists more broadly bolster antioxidant defences via the Nrf2/ARE pathway and reduce endoplasmic reticulum stress through modulation of the PERK pathway.

Genetic evidence adds weight to the GIP connection. A two-sample Mendelian randomisation analysis found that genetic activation of the GIP receptor is associated with a reduced risk of PCOS, and animal work shows that GIP signalling regulates the oestrous cycle and female fertility through the pituitary-gonadal axis. The gut microbiome may also be a critical link: dysbiosis in PCOS elevates the microbial metabolite agmatine, which activates the farnesoid X receptor and suppresses GLP-1 secretion from intestinal L cells, contributing to insulin resistance and ovarian dysfunction. This agmatine-FXR-GLP-1 axis offers a compelling explanation for how gut health, metabolism and reproduction converge in the syndrome.

Beyond the ovary, incretins display striking anti-inflammatory and anti-fibrotic properties with direct relevance to uterine disease. GLP-1 suppresses macrophage inflammatory factors including IL-1beta, IL-6 and TNF-alpha, and gene therapy studies in obese diabetic mice showed reduced macrophage infiltration of adipose tissue and inhibition of NF-kappaB and JNK signalling. In models of intrauterine adhesion, semaglutide alleviated fibrosis and inflammation by modulating NF-kappaB and reducing fibrotic markers such as ACTA2, COL1A1 and FN, while dulaglutide improved endometrial thickness and reduced collagen deposition by suppressing M1 macrophage polarisation and the TGF-beta/Smad2 pathway. Preclinical studies likewise suggest GLP-1 receptor agonists can inhibit the proliferation of ectopic endometrial cells in endometriosis through PI3K/Akt and NF-kappaB pathways.

The anti-tumour signals are tantalising but preliminary. In endometrial cancer cell lines, liraglutide inhibited proliferation in a time- and concentration-dependent manner, activating AMPK, upregulating progesterone receptors and synergising with medroxyprogesterone acetate. Autophagy appears central: liraglutide induced autophagic cell death by increasing LC3 expression and p-AMPKalpha while decreasing SQSTM1. For ovarian cancer, GLP-1 receptor expression has been documented in some tumour tissues, and agonists can curb proliferation and invasion via AMPK in vitro—but the authors are careful to stress that these anti-tumour effects may be partly secondary to weight loss and improved metabolic status, and direct effects require clinical validation.

Perhaps the most conceptually ambitious frontier is the brain-gut axis. Incretins directly modulate the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, and electrophysiological recordings show GLP-1 acting on GnRH neurons to increase firing rates and GABAergic synaptic input. GLP-1 receptor agonists may increase pulsatile GnRH release via the hypothalamic kisspeptin system, influencing luteinising hormone secretion, while peripherally promoting follicular development and oocyte maturation through effects on theca cells. GIP receptor knockout mice exhibit disrupted oestrous cycles and reduced fertility, underscoring GIP’s non-redundant role. Notably, a dual GLP-1/oestrogen agonist improved ovarian cyclicity and insulin sensitivity in PCOS mouse models without direct estrogenic proliferative effects on the uterus.

Clinical translation, however, demands caution. Combination therapy with metformin outperforms metformin alone for weight, BMI and insulin sensitivity, and semaglutide reduced lingual fat in women with PCOS in a randomised trial—yet adverse events are more frequent with combination regimens, and real-world data show 17.8% of patients are non-responders to semaglutide or liraglutide for obesity. Gastrointestinal symptoms remain the most common side effects, and safety concerns persist regarding gallbladder disorders, pancreatitis and rodent C-cell findings. Use in pregnancy and lactation is not recommended, with regulators advising contraception and a two-month washout before conception. For endometriosis, intrauterine adhesions and gynaecological cancers, the evidence remains almost entirely preclinical. The authors call for large, multicentre randomised trials with reproductive outcomes as primary endpoints, dedicated exploration of dual GIP/GLP-1 agonists such as tirzepatide, and tissue-specific studies to disentangle direct hormonal actions from the indirect fruits of metabolic improvement. Incretin-based therapy, they conclude, represents a promising interdisciplinary bridge between endocrinology and gynaecology—one whose full span has yet to be built.

Subject of Research: The role and mechanisms of the incretin hormones GLP-1 and GIP in gynaecological diseases

Article Title: The Role and Mechanism of Incretins in Gynaecologic Diseases

Article References: Yan, J., Cao, M., Ding, Y., Zhang, Y., Sun, Y., Jiang, G., Zhang, Y., Kang, L., Zhou, X., Luo, J., & Li, B. (2026). The Role and Mechanism of Incretins in Gynaecologic Diseases. Endocrinology, Diabetes & Metabolism, 9(5), Article e70340. https://doi.org/10.1002/edm2.70340

Image Credits: AI Generated

DOI: 10.1002/edm2.70340

Keywords: incretins, GLP-1, GIP, polycystic ovary syndrome, endometrial cancer, endometriosis, intrauterine adhesions, insulin resistance, brain-gut axis, GLP-1 receptor agonists, semaglutide, women's health