Abstract Polyendocrine metabolic ovarian syndrome (PMOS) is a complex endocrine–metabolic disorder affecting up to 18% of women worldwide and remains the leading cause of anovulatory infertility. Despite extensive research, current treatments primarily target symptoms, including menstrual irregularities, hyperandrogenism, and metabolic dysfunction, without addressing the underlying molecular and tissue-level disturbances. Advances in multi‑omic profiling have identified disruptions across neuroendocrine, metabolic, inflammatory, and extracellular matrix pathways, alongside genetic susceptibility at loci such as DENND1A , CYP17A1 , LHCGR , FSHR , IRS1 , and PPARG . However, the functional roles of many variants remain unresolved. CRISPR/Cas9 gene editing enables precise interrogation of these pathways, while stem cell–based platforms, including mesenchymal stem cells (MSCs), exosomes, and gene-edited induced pluripotent stem cells (iPSCs), may serve as complementary platforms for regeneration and disease modeling. Preclinical studies demonstrate that MSCs and their derivatives modulate inflammation, restore ovarian structure, and improve metabolic parameters, while iPSC-based models enable patient-specific investigation of steroidogenic and metabolic abnormalities. Translational challenges remain, including targeted delivery, off-target effects, phenotypic heterogeneity, and regulatory considerations. Integrating CRISPR‑based functional genomics with stem cell research may shift PMOS management from symptom‑focused care to targeted, mechanism‑driven interventions that could modify the course of PMOS (Graphical Abstract). Graphical Abstract Mapping the paradigm shift from symptomatic management to mechanism-driven precision medicine in Polyendocrine Metabolic Ovarian Syndrome (PMOS). The left panel summarizes current clinical challenges defined by purely symptomatic treatments for anovulatory infertility, hyperandrogenism, and metabolic dysfunction, a limitation sustained by a historically poor understanding of underlying disease mechanisms. The middle panel outlines novel biotechnological platforms for mechanistic discovery and therapeutic intervention. Gene function interrogation uses CRISPR/Cas9 editing to target specific risk loci, including DENND1A , CYP17A1 , IRS1 , and PPARG , to dissect functional pathways governing androgen excess, follicular arrest, and insulin resistance. Stem cell-based strategies employ mesenchymal stem cells (MSCs) and MSC-derived exosomes to modulate systemic inflammation, restore ovarian physiological function, and improve homeostatic metabolic parameters. Patient-specific disease modeling utilizes induced pluripotent stem cells (iPSCs) differentiated into granulosa-like cells or in vitro endometrial models to recapitulate distinct steroidogenic and metabolic abnormalities. The right panel illustrates the ultimate clinical goal of these integrated approaches, demonstrating how transitioning to targeted therapies establishes a balanced endocrine-metabolic profile, improves reproductive function, and reduces long-term metabolic risks, successfully moving the field toward mechanism-driven care and precision medicine. This figure was created with BioRender.com.
Khatun et al. (Tue,) studied this question.