Stigmasterol alleviates central precocious puberty by targeting the IGF-1/PI3K/Akt/mTOR signaling pathway and modulating the Kisspeptin/GnRH axis

Stigmasterol was found to counteract central precocious puberty in a rat model and in hypothalamic neurons by suppressing IGF-1/PI3K/Akt/mTOR signaling and modulating the Kisspeptin/GnRH axis, supporting its potential as a multi-target natural candidate. The study combined computational predictions with experimental validation in animals and cells.

Journal article — Preclinical in silico, in vivo, in vitro study. Population: N-Methyl aspartic acid-induced CPP rat model and GT1-7 hypothalamic neurons. Interventions: Stigmasterol.

Favorable binding of stigmasterol to IGF-1/PI3K/Akt/mTOR core proteins was predicted by docking and dynamics simulations. In the rat CPP model, stigmasterol delayed vaginal opening, lowered serum estradiol and testosterone, and improved uterine and ovarian histopathology while suppressing hypothalamic pathway overactivation and neuronal apoptosis. In GT1-7 cells, stigmasterol reduced high-glucose high-fat-induced proliferation, inflammatory cytokines, and apoptosis, and altered expression of puberty-related genes including Kisspeptin/GnRH components. Co-treatment with 740YP partially reversed stigmasterol's protective effects. No numerical values are reported in the abstract.

Researchers studying Kisspeptin would care because this paper links stigmasterol's effect on central precocious puberty to modulation of the Kisspeptin/GnRH axis, offering a potential phytosterol probe for this pathway. It does not establish stigmasterol as a clinical treatment, and the precise molecular interaction with kisspeptin neurons remains to be defined.

Key findings

• In silico analyses showed favorable binding of stigmasterol to core proteins in the IGF-1/PI3K/Akt/mTOR pathway.
• In vivo, stigmasterol significantly delayed vaginal opening and reduced serum estradiol and testosterone in the CPP rat model.
• Stigmasterol suppressed hypothalamic overactivation of IGF-1/PI3K/Akt/mTOR and attenuated neuronal damage and apoptosis.
• In vitro, stigmasterol inhibited high-glucose high-fat-induced proliferation, inflammatory cytokine release, and apoptosis in GT1-7 cells.
• The PI3K agonist 740YP attenuated selected protective effects of stigmasterol, implicating PI3K/Akt/mTOR in its mechanism.

Limitations

• Preclinical study only; findings may not translate to humans.
• No clinical dose, pharmacokinetics, or safety data are provided.
• Sample size and treatment duration are not reported in the abstract.
• In silico predictions require further experimental validation.

The record

• Journal: Biochimica et biophysica acta. Molecular basis of disease: 168398
• Published: 2026-08-06
• PMID: 42562054 — DOI: 10.1016/j.bbadis.2026.168398
• Author countries: China

Peptide profiles: Kisspeptin.

All indexed evidence: Kisspeptin trials & papers.

Related studies: Neurotransmitter and neuromodulator imbalance in kisspeptin/GnRH regulation in rodent…, Chronic subcutaneous kisspeptin-10 stimulates gonadotropin secretion for 12 days in…, Dlk1-deficient mice achieve puberty despite low body weight and low levels of leptin and…, Kisspeptin System: A Modulator of Neuroinflammation and Behaviour in Temporal Lobe….