Evidence for KISS-1 nuclear translocation and PI3K/AKT signaling in the ultrastructurally and morphometrically analyzed human endometriosis

Rasim Hamutoğlu, Celal Kaloğlu, Hüseyin Eray Bulut, Çağlar Yıldız
Frontiers in cell and developmental biology · 2026 · vol. 13 , pp. 1625031 · doi:10.3389/fcell.2025.1625031 · PMID:41567980 · PMC12816297 · W7118625761
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This study found increased PI3K/AKT signaling and nuclear translocation of KiSS-1 in endometriotic tissues, suggesting a link to cellular stress, fibrotic remodeling, and potentially representing a therapeutic target.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This prospective study compared control, eutopic, and ectopic endometrial biopsies from 27 women (18 controls, 9 with ovarian endometriosis) to examine whether KISS-1 nuclear localization relates to PI3K/AKT pathway activity, using immunofluorescence with semi-quantitative scoring alongside transmission electron microscopy and morphometric analysis of tissue remodeling. The authors found increased PI3K and AKT expression in both eutopic and ectopic endometrium in endometriosis, along with reduced KiSS-1 expression that localized to the nucleus in a subset of cells, while TEM showed stress-associated features such as autophagy-related vesicles, mitochondrial disruption, and altered nuclear architecture. Morphometry indicated fibrotic remodeling in ectopic tissue, with decreased glandular volume and increased stromal matrix content (p < 0.05), while a key limitation was the reliance on semi-quantitative scoring rather than automated ImageJ quantification due to technical constraints. This paper is centrally about endometriosis — it analyzes PI3K/AKT activity and KISS-1 nuclear translocation in eutopic and ectopic endometrial tissues and links them to ultrastructural stress responses and fibrotic remodeling in ovarian endometriosis.

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Abstract

BACKGROUND: Endometriosis is a common estrogen-dependent disease marked by ectopic endometrial growth. Although the PI3K/AKT and kisspeptin pathways are known to regulate endometrial homeostasis, their interplay in disease progression remains unclear. This study investigated the relationship between nuclear Kisspeptin (KiSS-1) localization and PI3K/AKT pathway activity in endometriotic tissues, focusing on stage-specific cellular alterations. METHODS: In this prospective study, control, eutopic and ectopic endometrial biopsies were collected from 27 women (18 controls, 9 with ovarian endometriosis). Histopathological assessments were performed using JB4 embedding, immunofluorescence, and transmission electron microscopy. Morphometric analyses were used to quantify structural alterations. RESULTS: In both eutopic and ectopic endometrium from patients with endometriosis, PI3K and AKT expression levels were significantly increased, whereas KiSS-1 expression was reduced and showed nuclear localization in a subset of cells. TEM analysis revealed features consistent with cellular stress, including autophagy-related vesicles, mitochondrial structural disruption, and alterations in nuclear architecture. Morphometric evaluation demonstrated a fibrotic remodeling in ectopic tissue. Specifically, glandular volume decreased, while stromal matrix content increased (p < 0.05). CONCLUSION: These findings suggest a mechanistic link between PI3K/AKT signaling and nuclear KiSS-1 translocation as an adaptive response to chronic hypoxia and inflammation in endometrial cells. This interaction may regulate survival, proliferation, and fibrotic remodeling processes characteristic of endometriosis. This integrated ultrastructural and molecular analysis provides novel insights into the pathophysiological role of nuclear KiSS-1 and its potential as a diagnostic and therapeutic target in endometriosis.

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endometriosis

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