Published Research
The KISS1/KISS1R Axis in Human Placentation: Molecular Mechanisms and Implications for Foetal Growth Restriction and Pre-Eclampsia.
Gyokova E, Hristova-Atanasova E, Dimitrova K — 2026
Pre-eclampsia and foetal growth restriction (FGR) are major pregnancy complications primarily driven by placental dysfunction, and remain leading causes of maternal and perinatal morbidity. Ultrasound imaging, Doppler studies, and angiogenic biomarkers like placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) constitute the main diagnostic modalities; however, these predominantly reflect established disease rather than early molecular disturbances underlying placentation. The identification of biomarkers directly associated with trophoblast signalling pathways has the potential to improve early risk stratification and enable mechanistic classifications. Kisspeptin signalling via its receptor (KISS1R) regulates trophoblast invasion, extracellular matrix remodelling, ERK1/2 activation, and angiogenic balance, thereby modulating spiral artery transformation. Kisspeptin-10 (KP-10), the minimal bioactive fragment of KISS1, is highly expressed in placental syncytiotrophoblasts and exerts its effects through the G-protein-coupled receptor KISS1R. Core features of early-onset FGR and pre-eclampsia (PE)-including defective placentation, maternal vascular malperfusion, and angiogenic imbalance-have been linked to dysregulation of this pathway. During normal gestation, maternal circulating kisspeptin concentrations rise exponentially. In contrast, pregnancies subsequently complicated by FGR or PE, particularly in the early gestation, are associated with reduced levels. However, the comparability of existing studies and their translational applicability are limited by a substantial methodological heterogeneity, including assay variability, gestational age dependence, and inadequate adjustment for maternal confounders. These limitations hinder robust conclusions regarding the role of kisspeptin in placental pathology. This review critically integrates molecular, pathophysiological, and clinical evidence relating to the role of KP-10 in placental dysfunction. The key question is whether KP-10 represents a mechanistic biomarker of trophoblast signalling dysfunction or merely a secondary marker of reduced placental mass; resolving this distinction is essential.
Metabolic-endocrine correlates of gut-brain axis mediators in polycystic ovary syndrome: A case-control study.
Bashir R, Asrar M, Kamboj S, Yousuf A, Arif T, et al. — 2026
Polycystic ovary syndrome (PCOS) is increasingly recognized as a neuro-metabolic disorder involving disrupted signaling between the brain-gut axis and reproductive system. Peptides such as kisspeptin, ghrelin, serotonin, and peptide tyrosine tyrosine (PYY) are emerging as integrators of metabolic and endocrine function, yet their coordinated alterations in PCOS and relevance to metabolic risk remain underexplored. Therefore, we investigated the combined pattern of serum kisspeptin, ghrelin, serotonin, and PYY in PCOS, and their associations with metabolic and hormonal indices. In this case-control study, a total of 190 women aged 18-40 years were included between June 2023 and June 2024, comprising 96 women diagnosed with PCOS according to 2003 Rotterdam criteria and 94 age-matched healthy controls. Serum levels of kisspeptin, ghrelin, serotonin, and PYY were measured using ELISA. Secondary assessments included clinical, metabolic, hormonal, and inflammatory parameters. Women with PCOS had significantly higher serum kisspeptin levels and lower ghrelin and serotonin levels compared to controls (p < .05), while PYY levels were similar between the groups. Kisspeptin was inversely correlated with ghrelin (r = -.237, p = .003) and serotonin (r = -.303, p < .001). These peptides also showed significant associations with metabolic indices such as fasting insulin, glucose, HOMA-IR, triglyceride-glucose (TyG), and TyG-BMI ratios. In regression models adjusted for BMI, lower ghrelin (OR = 0.661, p = .008) and serotonin (OR = 0.814, p = .016) levels were independently associated with higher odds of PCOS. Exploratory receiver operating characteristic (ROC) analysis showed that kisspeptin demonstrated moderate discriminatory performance for PCOS (AUC = 0.768; 95% CI: 0.696-0.839), with 82.4% sensitivity and 59% specificity, whereas ghrelin, serotonin, and PYY showed lower AUCs, reflecting limited stand-alone discriminatory ability. Elevated kisspeptin with concomitant reductions in ghrelin and serotonin define a reproducible peptide signature in PCOS, linking neuroendocrine perturbations to measurable metabolic risk, independent of obesity. While kisspeptin shows greater biological separation between groups, none of the peptides alone are sufficient for diagnostic classification; instead, they indicate the central role of hypothalamic-gut axis dysfunction, particularly in lean PCOS phenotypes.
Kisspeptin-10 attenuates pulmonary arterial hypertension via restoration of mitochondrial function in pulmonary artery smooth muscle cells.
Huang S, Chen Z, Gong W, Song Y, Ding W, et al. — 2026
Mitochondrial dysfunction and dysregulated mitophagy in pulmonary artery smooth muscle cells (PASMCs) critically drive pulmonary arterial hypertension (PAH). Here we show that Kisspeptin-10, acting via its receptor GPR54, markedly attenuates PAH in the SU5416/hypoxia mouse model. The administration of kisspeptin-10 resulted in a considerable reduction in the systolic pressure of the right ventricle, as well as in the level of right ventricular hypertrophy and pulmonary vascular remodeling. Mechanistically, Kisspeptin-10 restored mitochondrial membrane potential, ATP production, and cytochrome c oxidase activity in hypoxic PASMCs and PAH lungs while normalizing excessive accumulation of the mitophagy proteins PINK1, Parkin, and FUNDC1. In vitro, Kisspeptin-10 directly inhibited hypoxia-induced PASMC proliferation. Therefore, Kisspeptin-10 is able to alleviate experimental PAH predominantly by recovering mitochondrial homeostasis and limiting aberrant mitophagy in PASMCs. This provides evidence that the Kisspeptin/GPR54 axis is a potential therapeutic target in PAH.
Relationship between kisspeptin-10, neurokinin B and dynorphin A in the course of normal and delayed puberty in ewes.
Szysiak N, Kosior-Korzecka U, Greguła-Kania M, Patkowski K, Fila M, et al. — 2026
INTRODUCTION: Kisspeptin (KiSS), neurokinin B (NKB) and dynorphin A (Dyn A) participate in the neuroendocrine regulation of reproductive system development and functioning; however, their roles in the onset of sexual maturity and pathomechanism of delayed puberty have not yet been fully elucidated. The aim of the study was to determine changes in the kisspeptin-10 (KiSS-10), NKB and Dyn A concentration in blood plasma collected from ewe lambs during puberty in relation to the first ovulation time, and to examine the relationship between these neuropeptides. MATERIAL AND METHODS: Twenty-four ewe lambs were divided into two groups: from single (S) pregnancies and from twin (T) pregnancies. To determine the KiSS-10, NKB and Dyn A concentration with ELISA, blood was collected from all sheep at 4, 5, 6, 7, 8, 9 and 10 months of age. Singletons and twins had their first ovulations at 8 and 10 months of age, respectively. RESULTS: Changes in the KiSS-10 and NKB concentrations were positively correlated with age in both S (r = 0.86) and T ewes (r = 0.89). A negative correlation was found between KiSS-10 and Dyn A (r = -0.55 and -0.98, for S and T, respectively) and between NKB and Dyn A (r = -0.89 and -0.94, for S and T, respectively). CONCLUSION: The initiation of ovarian activity is associated with concurrent increases in plasma KiSS-10 and NKB concentrations with age and reduced Dyn A concentrations in both groups. Our results show that these neuropeptides may regulate the timing of reproductive activity onset in sheep.
Kisspeptin-10 Promotes Hormone Secretion, Ovarian Follicles Development and Fecundity via PI3K/AKT/ERK Signal Pathway in Mice.
Suocheng W, Linglong X, Jingshuang G, Zhenya G, Yuan C — 2026
OBJECTIVES: The present study aimed to comprehensively elucidate how KP-10 modulates hormone secretion, the proliferation and autophagy of ovarian follicles by regulating in-vivo and in-vitro levels of associated genes and proteins. METHODS: Follicular granulosa cells (FGCs) were cultured in EMDM/F12 medium. The proliferation viability, apoptosis, and autophagy rates of FGCs were determined, respectively. For in-vivo tests, 0, 5, 10, 20, 40 μg/g of KP-10 were injected into 75 mice allocated into control group (CG) and four KP-10 treated groups (including KP-1, KP-2, KP-3, and KP-4 groups). Maximum transverse diameter (MTD), maximum longitudinal diameter (MLD) and follicle-wall thickness (FWT) of secondary follicles were measured in days 0, 5, 10, 15, and 25. RT-qPCR and Western blot were employed to determine the contents of genes and proteins. RESULTS: The KP-10-treated groups exhibited increased FGCs proliferation, accompanied by decreased apoptosis and autophagy rates as compared with the control group (CG). The expression levels of KISS1R, Bcl-2, LC3-II, mTOR, p62/Sqstm1, PI3K, AKT, and ERK genes and proteins in FGCs were significantly enhanced (p < 0.05). Additionally, the number of secondary follicles, MTD, MLD, FWT, and the serum concentrations of progesterone and estradiol were notably elevated (p < 0.05). Moreover, the in-vivo levels of PI3K, AKT, ERK mRNAs, as well as StAR and CYP11A1 genes and proteins, were significantly higher than those in CG. FGCs proliferation in KP-10-treated groups was increased with reduction of apoptosis and autophagy rates. Levels of KISS1R, Bcl-2, LC3-Ⅱ, mTOR, p62/Sqstm1, PI3K, AKT and ERK genes and proteins in FGCs were enhanced (p < 0.05). Numbers of the secondary follicles, MTD, MLD, FWT and serum concentrations of progesterone and estradiol were significantly promoted (p < 0.05). In-vivo levels of PI3K, AKT, ERK mRNAs, StAR and CYP11A1 genes and proteins were accelerated as compared to CG. CONCLUSIONS: KP-10 accelerated the proliferation and suppressed the apoptosis and autophagy of FGCs, facilitated the development of the secondary follicles, and nd enhanced the synthesis and secretion of P4 and E2. Ten microgram per gram KP-10 had the best efficacy. Our study first time explored comprehensively the effects and mechanisms KP-10 in-vitro and in-vivo regulating reproductive hormone secretion, ovarian follicles development and fecundity in mice. These effects of KP-10 were achieved probably by activation of PI3K/AKT/ERK signal pathway. The findings held great promise for improving the reproductive function and fecundity of both animals and humans.