Long-chain fatty acids as functional modulators in PCOS: metabolic crosstalk, signaling pathways, and therapeutic...

Polycystic ovary syndrome (PCOS), a prevalent endocrine-metabolic disorder, exhibits dysregulated lipid metabolism with distinct alterations in long-chain fatty acids (LCFAs) profile. Heterogeneous profile of LCFAs dysregulation manifest in distinct PCOS phenotypes: Saturated fatty acids (SFAs) preferentially accumulate in serum and follicular fluid (FF) of insulin-resistant/hyperandrogenic (IR/HA) subtypes, exacerbating lipotoxicity, inflammatory responses, and ovarian impairment; monounsaturated fatty acids (MUFAs) display compensatory elevation yet demonstrate context-dependent effects regulated by stearoyl-CoA desaturase-1 (SCD1) activity; and polyunsaturated fatty acids (PUFAs) exhibit subtype-dependent actions: n-3 derivatives (EPA/DHA) ameliorate metabolic dysfunction, resolve inflammation, and enhance ovarian competence, whereas pro-inflammatory n-6 PUFAs elevate the n-6/n-3 ratio, disrupting follicular homeostasis. In PCOS, dysregulation of LCFA transport receptors, including fatty acid-binding proteins 4/5 (FABP4/5), CD36, are associated with insulin resistance (IR) and hyperandrogenemia (HA) through obesity-independent mechanisms. Sensing receptors GPR120 and GPR40 critically orchestrate insulin sensitivity, inflammatory cascades, and reproductive function, highlighting their therapeutic relevance in PCOS pathophysiology. Although direct evidence remains limited, targeting these pathways may represent a promising strategy to concurrently mitigate HA, IR, and dyslipidemia in a phenotype-specific manner, warranting further preclinical and clinical investigations. Future investigations should focus on defining and validating clinical biomarkers, tissue-specific receptor functions, and evaluating targeted interventions in distinct PCOS phenotypes.