Long-chain acyl-CoA synthetases in female reproductive diseases: isoform-specific regulation of lipid metabolism, ferroptosis, and inflammatory signaling.

Abstract

Female reproductive diseases (FRDs) substantially affect women's health and fertility, with lipid metabolic reprogramming emerging as a shared pathological feature. Long-chain acyl-CoA synthetases (ACSLs) activate long-chain fatty acids and direct lipid flux toward β-oxidation, lipid synthesis, and phospholipid remodeling, thereby influencing oxidative stress, ferroptosis, and inflammatory signaling. Unlike previous reviews centered on broad ACSL biology, selected isoforms, or pathway-based ferroptosis mechanisms, this review adopts a disease-spanning, isoform-specific framework. We compare ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6 across cervical, ovarian, and endometrial cancers, polycystic ovary syndrome, endometriosis, and preeclampsia. By integrating isoform-specific substrate preference, subcellular localization, and lipid-channeling functions, we examine how individual ACSLs differentially regulate fatty acid oxidation, lipid synthesis and phospholipid remodeling, ferroptosis sensitivity, and inflammatory signaling across reproductive disease contexts. We further distinguish disease-specific experimental evidence from bioinformatic associations and mechanistic extrapolations from other disease models. Current evidence most consistently supports a disease-relevant role for ACSL4 in ferroptosis regulation, whereas ACSL1, ACSL3, ACSL5, and ACSL6 show greater context dependence. This integrated framework identifies shared metabolic mechanisms, disease-specific differences, and priorities for cell-resolved validation and future isoform-selective therapeutic development.

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