Orchestrating the gut microbiota-mitochondrial-immune axis in gynecological diseases: mechanisms and dual-targeting therapeutic strategies.

The "gut microbiota-mitochondria axis" has become the core hub connecting the metabolism, immunity, and endocrine regulation of gynecological diseases. In this review, the hierarchical regulation mechanism of this axis is systematically combed: at the upstream level, intestinal short-chain fatty acids (SCFAs), bile acids (BAs), tryptophan derivatives, and other metabolites can activate AMPK/PGC-1α, FXR/TGR5, and AhR-mediated energy sensing and receptor signaling pathways; On the functional level, bacterial lipopolysaccharide-TLR4 signal and cGAS-STING/NLRP3 inflammasome pathway activated by cytoplasmic mitochondrial DNA (mtDNA) can amplify innate immune response; At the effect level, mitochondrial reactive oxygen species (ROS), mitochondrial dynamics, and PINK1/Parkin-mediated mitophagy are the common key nodes to regulate mitochondrial quality and inflammatory response. Combined with the two-way relationship between the estrobolome and steroid production, the above processes together form a self-reinforcing closed loop of "metabolic input-immune amplification-oxidative stress/autophagy-endocrine regulation". Based on this theoretical framework, this paper analyzes the disease-specific correlations among polycystic ovary syndrome, endometriosis, premature ovarian insufficiency, and gynecological malignancies, and puts forward a dual-targeted treatment idea with research value. The intervention plan with microbiota as the core aims to adjust the metabolite spectrum and endotoxin level; Mitochondria-centered interventions focus on restoring cell energy metabolism and apoptosis sensitivity. In addition, this review constructs a hierarchical research framework of "microbiota-metabolomics-mitochondria" to clarify the targeted phenotypes in the pathway, and provide guidance for subsequent clinical trial design and long-term monitoring. With the deep integration of multi-omics technology and targeted interventions, the gut microbiota-mitochondria axis is expected to become an important breakthrough in precision medical treatment of gynecological diseases and build a brand-new bridge between basic mechanism research and clinical transformation.