KP-10(Southern Medical University)

Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular junctions. While neuroendocrine-immune system dysfunction plays a crucial role in the development of autoimmune diseases, its involvement in MG remains largely unexplored. Kisspeptin, a neuropeptide hormone and endogenous ligand for GPR54 receptor, has been demonstrated to regulate antitumor immunity, antiviral immunity, and several autoimmune diseases. However, the role and mechanism of kisspeptin in MG remain to be elucidated.

Serum kisspeptin levels were measured by ELISA in MG patients and experimental autoimmune myasthenia gravis (EAMG) rats. EAMG rats were treated with KP10 (kisspeptin analog) to evaluate its effects on body weight, clinical scores, grip strength, antibody levels, and complement deposition. Hypothalamic Kiss1 expression was assessed using Western blot and immunofluorescence. Stereotactic injection of adeno-associated virus overexpressing Kiss1 was performed to study its regulatory effects on disease progression. CD4⁺ T cell transfer via tail vein, Western blot, and flow cytometry were employed to investigate KP10's modulatory effects on CD4⁺ T cell subsets and the NF-κB signaling pathway.

Kisspeptin expression was significantly decreased in both MG patient sera and EAMG rat sera, with reduced hypothalamic Kiss1 expression in EAMG rats. Either hypothalamic Kiss1 overexpression or intraperitoneal KP10 administration significantly improved clinical signs in EAMG rats. Further in vivo and in vitro studies revealed that KP10 ameliorated EAMG clinical signs by modulating Th1/Th17/Treg cell balance through inhibition of NF-κB signaling pathway activation in CD4⁺ T cells.

This study elucidates that Kisspeptin secreted by hypothalamic participates in MG pathogenesis through the Kisspeptin-GPR54-NF-κB signaling axis by regulating CD4⁺ T cell subset balance, suggesting that the kisspeptin/GPR54 pathway may serve as a potential therapeutic target for MG treatment.

Kisspeptin and its cognate G-protein-coupled receptor (GPCR), the kisspeptin-1 receptor (KISS-1R), are central to mammalian reproduction, regulating the hypothalamic-pituitary-gonadal axis. They are upstream regulators of gonadotropin-releasing hormone (GnRH) secretion, a hallmark of the onset of puberty, subsequently tuning luteinizing hormone and follicle-stimulating hormone levels and bringing about steroid hormone production. In mammals, kisspeptin (Kp) is synthesized as a 145-mer pre-pro-polypeptide by the KISS1 gene, which further undergoes cleavage to form four kisspeptin isoforms: Kp-54, Kp-14, Kp-13 and Kp-10. They all share a common decapeptide sequence (Kp-10), followed by an RF-amide in their C-terminal end. Kp-10, the smallest isoform, is reported to activate KISS-1R to its full functional potential. The reproductive roles of Kp-54 and Kp-10 have been studied extensively by in vivo and clinical studies owing to their longer terminal half-life and commercial bargain, respectively. This comprehensive review aims to collate the multitude of functions displayed by all naturally occurring kisspeptin isoforms and other kisspeptin-like peptides in reproduction and beyond, including metabolic regulation and therapeutic potential. The structural architecture of kisspeptin isoforms reported using alanine scan substitution studies and secondary structure using circular dichroism and nuclear magnetic resonance spectroscopy studies have also been highlighted. Several kisspeptin agonists and antagonists have been developed for ovulation induction in assisted reproduction and management of pubertal disorders. This review summarizes the diverse roles and structural insights of kisspeptin isoforms to help in the identification of new horizons and thematic areas for basic and translational research, culminating in potential therapeutic applications.