Proteoformics-driven new concept of human growth hormone in clinical endocrinology.

Growth hormone (GH) is a multifunctional regulator in somatic growth, metabolism, and tissue repair. Its pulsatile secretion is regulated by hypothalamic GH-releasing hormone (GHRH) and somatostatin (SST), and feedback inhibition by insulin-like growth factor 1 (IGF-1). Dysregulation of GH underlies several clinical disorders, including GH deficiency (GHD), acromegaly, and gigantism. The emerging concept of proteoformics has fundamentally reshaped the traditional view of GH: although human GH is encoded by a single gene, it gives rise to multiple proteoforms (GHPs) with distinct biological activities. In-depth study on GHPs pattern benefits understanding its precise molecular mechanism, discovering new therapeutic targets/drugs, and constructing GHPs-based biomarkers. Integration of proteoformics with multi-omics facilitates the construction of dynamic regulatory networks for GH signaling, thereby providing robust support for biomarker discovery and precision medicine strategies in GH-related diseases. Proteoform-based personalized therapy holds promise to advance current treatments such as somatostatin receptor ligands (SRLs), growth hormone receptor (GHR) antagonists, and long-acting GH formulations, with emerging therapies like antisense oligonucleotides and oral GHRH agonists showing preliminary promise. This review examines the potential role of proteoform-centered multi-omics in advancing personalized diagnosis and treatment, discusses challenges in clinical translation, and outlines a roadmap for integrating GH proteoformics into predictive, preventive, and personalized medicine (3PM).