| Pathway/Mechanism | Key Molecular Players | Cellular/Tissue Location | Normal Function in Puberty | Alteration in CPP | GO/CL Term Suggestions |
|---|---|---|---|---|---|
| Kisspeptin-GnRH activation axis | KISS1, KISS1R/GPR54, GnRH, LH, FSH | Hypothalamic kisspeptin neurons projecting to GnRH neurons; pituitary gonadotrophs; gonads (pqac-00000001, pqac-00000003, pqac-00000012) | Kisspeptin is a major upstream activator of GnRH neurons, promoting pulsatile GnRH release, pituitary gonadotropin secretion, and pubertal HPG-axis reactivation (pqac-00000001, pqac-00000003, pqac-00000012) | Premature or excessive activation of this pathway causes early HPG-axis activation; rare activating variants in KISS1R and KISS1 prolong signaling and can trigger CPP (pqac-00000003, pqac-00000013) | GO:0005184 neuropeptide hormone activity; GO:0004969 gonadotropin-releasing hormone receptor activity; GO:0060016 positive regulation of hormone secretion; CL:0000548 neuron |
| KNDy pulse generator network | Kisspeptin, neurokinin B (TAC3/NKB), dynorphin (PDYN/Dyn) | Arcuate nucleus KNDy neurons in hypothalamus; projections to GnRH neurons/dendrons (pqac-00000012, pqac-00000013) | KNDy neurons coordinate pulsatile GnRH output; NKB provides stimulatory and dynorphin inhibitory tone to shape pulse frequency and pubertal maturation (pqac-00000012) | Premature maturation or dysregulation of KNDy signaling is thought to increase GnRH pulse generator activity and advance pubertal onset in CPP (pqac-00000012, pqac-00000013) | GO:0007218 neuropeptide signaling pathway; GO:0060078 regulation of postsynaptic membrane potential; CL:0000700 neuroendocrine cell; CL:0000548 neuron |
| Imprinted inhibitory brake: MKRN3 | MKRN3 | Hypothalamic upstream regulators of GnRH secretion; neuroendocrine control network (pqac-00000003, pqac-00000013) | MKRN3 acts as an upstream inhibitor of GnRH secretion and helps maintain the prepubertal quiescent state (pqac-00000013) | Loss-of-function MKRN3 variants remove inhibitory restraint, enabling premature GnRH secretion; this is the most common known monogenic cause of CPP (pqac-00000003, pqac-00000013) | GO:0045892 negative regulation of transcription, DNA-templated; GO:0060013 negative regulation of gonadotropin secretion; CL:0000548 neuron |
| Imprinted inhibitory brake / Delta-Notch modulation: DLK1 | DLK1, NOTCH pathway components, ADAM17/TACE | Membrane-bound and soluble DLK1 in neuroendocrine and metabolic tissues; hypothalamic and circulating contexts (pqac-00000006, pqac-00000015) | DLK1 is an inhibitory regulator of Delta-Notch signaling and contributes to repression of pubertal initiation; circulating DLK1 normally decreases across puberty (pqac-00000006) | Loss-of-function DLK1 variants reduce inhibitory signaling and are a rare cause of familial CPP; some affected families also show metabolic abnormalities, linking reproduction and metabolism (pqac-00000006, pqac-00000010, pqac-00000015) | GO:0008593 regulation of Notch signaling pathway; GO:0060013 negative regulation of gonadotropin secretion; CL:0000548 neuron; CL:0002494 endocrine cell |
| Epigenetic control of pubertal timing | Polycomb group repressors, H3K27me3, KDM6B, miRNAs, epigenetic regulation of KISS1, MKRN3, DLK1 | Hypothalamic arcuate nucleus and other HPG regulatory centers (pqac-00000004, pqac-00000012) | Puberty timing depends on switching from repressive to permissive chromatin states at puberty-related genes; epigenetic mechanisms maintain childhood quiescence and allow later activation of the GnRH pulse generator (pqac-00000004, pqac-00000012) | Premature relief of epigenetic repression or altered regulation of imprinted genes may facilitate early KISS1/GnRH activation and CPP susceptibility (pqac-00000004, pqac-00000012) | GO:0040029 regulation of gene expression, epigenetic; GO:0016573 histone acetylation; GO:0031061 positive regulation of histone methylation; CL:0000548 neuron |
| Metabolic sensing via leptin-mTOR-AMPK-SIRT1 | Leptin, mTOR, AMPK, SIRT1, Kiss1 neurons | Hypothalamic Kiss1 neurons and afferent metabolic circuits (pqac-00000013) | Energy sufficiency signals permissive puberty onset; mTOR supports leptin's permissive action, whereas AMPK/SIRT1 mediate inhibitory effects of undernutrition on puberty timing (pqac-00000013) | Early obesity may prematurely activate Kiss1 pathways through altered mTOR/AMPK/SIRT1 signaling, advancing pubertal onset and contributing to CPP (pqac-00000013, pqac-00000000) | GO:0032008 positive regulation of TOR signaling; GO:0001932 regulation of protein phosphorylation; GO:0042593 glucose homeostasis; CL:0000548 neuron |
| Obesity/high-fat diet inflammatory-metabolic pathway | High-fat diet, adiposity, hypothalamic inflammation, microglia, phoenixin, Kiss1/GnRH network | Hypothalamus, adipose tissue, microglial cells, ovary (pqac-00000000) | Under normal conditions, nutritional cues help tune pubertal timing without pathological HPG-axis activation (pqac-00000000) | Childhood obesity and high-fat diet are associated with earlier puberty, possibly through hypothalamic inflammation, microglial activation, and altered GnRH network regulation; evidence is strongest in girls (pqac-00000000) | GO:0006954 inflammatory response; GO:0042063 gliogenesis; GO:0060012 synaptic transmission, hormonal regulation; CL:0000129 microglial cell |
| Ceramide-sympathetic ovarian pathway | Kisspeptin projections, paraventricular nucleus ceramide synthesis, sympathetic innervation of ovary | Hypothalamic paraventricular nucleus and ovary (pqac-00000005, pqac-00000013) | In normal physiology, metabolic-neuroendocrine integration coordinates ovarian maturation with central pubertal timing (pqac-00000013) | Obesity-associated pubertal precocity may occur not only through gonadotropin-dependent mechanisms but also through kisspeptin-linked ceramide/sympathetic pathways affecting the ovary (pqac-00000005, pqac-00000013) | GO:0030148 sphingolipid biosynthetic process; GO:0042220 response to cocaine?; GO:0001963 synaptic transmission, dopaminergic?; CL:0000117 autonomic neuron |
| Endocrine-disrupting chemical pathway | Perfluorinated compounds (PFCs/PFAS), estradiol, prolactin, HPG-axis regulators | Serum/exposome with endocrine effects on hypothalamus-pituitary-gonadal axis (pqac-00000002, pqac-00000004) | External chemical exposures normally should not perturb endocrine homeostasis or pubertal timing (pqac-00000004) | PFC exposure is associated with endocrine homeostasis imbalance, altered metabolic networks, and may contribute to CPP/PT pathogenesis through HPG-axis disruption (pqac-00000002) | GO:0071396 cellular response to lipid; GO:0008202 steroid metabolic process; CL:0002494 endocrine cell |
| Lipid, taurine, and arachidonic/glycerophospholipid metabolism | MMP9, TIMP1, SPP1, POSTN, COL1A1/COL2A1/COL6A1, BMP1; phosphocholine; arachidonic acid, linoleic acid, alpha-linolenic acid, taurine pathways | Circulating serum proteome/metabolome; extracellular matrix and skeletal-development related tissues (pqac-00000005) | Lipid and extracellular matrix remodeling likely participate in normal pubertal growth, skeletal maturation, and endocrine adaptation (pqac-00000005) | Omics studies in girls with CPP found differentially expressed proteins enriched in extracellular matrix, platelet degranulation, skeletal development, and downregulated immune response, with metabolites enriched in lipid and taurine pathways (pqac-00000005) | GO:0006629 lipid metabolic process; GO:0030198 extracellular matrix organization; GO:0001501 skeletal system development; CL:0000182 hepatocyte |
| Gut microbiome-metabolome-neuroendocrine axis | Gut microbes, Streptococcus, nitric oxide synthesis-related functions, fecal and blood metabolites | Gut microbiota, intestinal ecosystem, circulating metabolites, microbiota-gut-brain axis (pqac-00000009) | Gut microbiota can modulate endocrine, neural, and immune pathways that influence host neuroendocrine status (pqac-00000009) | CPP is associated with altered fecal microbiome and metabolite profiles; machine-learning classifiers based on microbes/metabolites showed AUCs 0.832-1.00, and nitric oxide synthesis emerged as a function linked to CPP progression (pqac-00000009) | GO:0006809 nitric oxide biosynthetic process; GO:0042592 homeostatic process; CL:0000084 enterocyte |
| Immune/extracellular matrix remodeling signature | Downregulated immune-response proteins; upregulated extracellular matrix and adhesion proteins | Circulating serum proteome (pqac-00000005) | Balanced immune and extracellular matrix signaling likely supports normal tissue remodeling during puberty (pqac-00000005) | CPP serum proteomics showed upregulation of extracellular matrix/cell adhesion/protein metabolic processes and downregulation of immune-response pathways, suggesting systemic remodeling accompanies early puberty (pqac-00000005) | GO:0006955 immune response; GO:0030198 extracellular matrix organization; CL:0000988 hematopoietic cell |


*Table: This table summarizes major neuroendocrine, genetic, epigenetic, metabolic, and systems-biology mechanisms implicated in central precocious puberty. It is useful for linking CPP pathophysiology to specific molecules, tissues, and ontology terms for knowledge-base annotation.*