One Fat-Activating Enzyme Emerges as a Common Thread in Female Reproductive Disease

A sweeping review of six female reproductive disorders has concluded that a single enzyme family member, ACSL4, currently carries the strongest and most reproducible disease-specific evidence of any long-chain acyl-CoA synthetase, while its four sibling isoforms remain largely unproven in these conditions. The analysis, published in Frontiers in Endocrinology, compares ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6 across cervical, ovarian, and endometrial cancers, polycystic ovary syndrome, endometriosis, and preeclampsia, and finds that the biological consequences of each enzyme depend far more on disease and cellular context than on the isoform itself.

Long-chain acyl-CoA synthetases sit at a critical junction of cellular metabolism. They catalyze the ATP-dependent activation of fatty acids containing roughly 12 to 20 carbon atoms, converting them into fatty acyl-CoAs at membrane-associated sites including the endoplasmic reticulum and the outer mitochondrial membrane. Once activated, these fatty acids can enter fatty acid oxidation for energy production, be channeled into lipid synthesis and storage, or be incorporated into membrane phospholipids. Because each isoform has a distinct substrate preference, subcellular localization, and tissue distribution, the review describes them as gatekeepers of lipid flux, deciding which metabolic route an activated fatty acid ultimately takes.

The review’s central argument concerns ferroptosis, an iron-dependent form of regulated cell death driven by the accumulation of lipid peroxides in cellular membranes. ACSL4 preferentially activates polyunsaturated fatty acids such as arachidonic acid and adrenic acid, generating PUFA-CoA derivatives that are incorporated into membrane phospholipids, particularly phosphatidylethanolamine, through remodeling enzymes such as LPCAT3. The resulting PUFA-containing phospholipids are highly vulnerable to iron-dependent oxidation, so ACSL4 activity effectively loads membranes with oxidizable substrate and sensitizes cells to ferroptosis. ACSL4-dependent arachidonic acid metabolism also feeds the pool of substrates used for eicosanoid synthesis, including prostaglandins and leukotrienes, providing a biochemical link between lipid remodeling and inflammatory signaling.

In cervical cancer, the review identifies direct functional support for ACSL4 in ferroptosis and treatment sensitivity. The circular RNA circLMO1 acts as a competing endogenous RNA that sponges miR-4291, relieving suppression of ACSL4; increased ACSL4 promotes ferroptosis and suppresses cervical cancer cell growth and metastatic behavior, and ACSL4 knockdown reverses these effects. In cervical squamous cell carcinoma, ACSL4 upregulation correlates with lipid ROS, ferrous iron, and malondialdehyde accumulation, together with downregulation of SLC7A11 and GPX4, enhancing sensitivity to cisplatin. Combined propofol and paclitaxel treatment also induced ferroptosis-associated changes in cervical cancer cells alongside increased ACSL4 expression, and a Lactobacillus crispatus-associated ferroptotic metabolic shift in SiHa cells included altered ACSL4 and LPCAT3 expression.

Ovarian cancer presents a more nuanced picture of ACSL4. In epithelial ovarian cancer models, ferroptosis-resistant cells can evade cell death by exporting ACSL4 protein through exosomes, with the sorting protein VIPAS39 facilitating this release; depleting VIPAS39 retains intracellular ACSL4, increases ferroptosis sensitivity, and suppresses xenograft tumor growth. At the same time, metastatic ovarian cancer-derived cells contain higher PUFA-lipid levels and greater ferroptosis susceptibility, and CRISPR screening identified ACSL4 as a driver of hematogenous metastatic extravasation by increasing PUFA-lipid abundance, membrane fluidity, and invasiveness. The review stresses that these findings are not contradictory but context-dependent: ACSL4-driven PUFA remodeling simultaneously enhances metastatic plasticity and creates dependence on enzymes such as ECH1, with combined ACSL4 and ECH1 inhibition markedly suppressing metastasis.

ACSL1 is the only other isoform with direct functional evidence in reproductive cancers. In endometrial cancer, ACSL1 is upregulated in human tumor tissues, and overexpression in endometrial cancer cells enhances fatty acid beta-oxidation and ATP production through the AMPK/CPT1C/ATP axis, promoting proliferation and migration. In ovarian cancer, proteomic comparisons of metastatic and non-metastatic cells showed that ACSL1-dependent myristoyl-CoA production promotes protein N-myristoylation, activating AMPK/Src signaling and enhancing fatty acid oxidation, and ACSL1 expression was higher in omental metastases than in primary tumors. By contrast, in cervical cancer ACSL1’s role rests mainly on methylation changes that increase with lesion progression, without established functional consequences.

In non-cancerous conditions, ACSL4 again dominates the evidence base, though the review is careful to distinguish marker-based findings from demonstrated cell death. In polycystic ovary syndrome models, dihydrotestosterone and insulin exposure altered ACSL4 expression in uterine tissue alongside GPX4 and glutathione depletion, increased malondialdehyde, iron deposition, and ferroptosis-associated mitochondrial changes. In granulosa-cell models, elevated palmitic acid promoted ER stress and ATF4/TXNIP signaling with increased ACSL4, DHEA-induced hyperandrogenic stress raised ACSL4 while reducing GPX4 and SLC7A11, and iron uptake through TFRC activated a NOX1 and PINK1 mitophagy pathway in which ACSL4 upregulation was required for mitophagy, GPX4 degradation, lipid peroxidation, and ferroptosis in KGN cells. Direct ACSL4 knockdown reduced lipid peroxidation in that context, and interventions including 1,25-dihydroxyvitamin D3 and nuciferine attenuated ferroptotic injury, although the review notes these should not be interpreted as direct ACSL4 inhibitors.

In endometriosis, the expression pattern of ACSL4 remains controversial, with some studies reporting upregulation in ectopic endometrial tissue and others observing no difference, a discrepancy the authors attribute to variations in sample size, tissue compartment, and patient characteristics. Elevated ACSL4 in the endometrium of patients with endometriosis has been associated with impaired endometrial receptivity, and ACSL4 inhibition improved receptivity markers and endometrial function. In preeclampsia, ACSL4 mRNA and protein were significantly increased in placental tissue from women with late-onset disease, particularly in the syncytiotrophoblast layer, alongside ferroptosis- and lipid-peroxidation-associated markers. More direct functional evidence comes from the METTL3/ACSL4 axis: METTL3-dependent m6A modification stabilized ACSL4 mRNA, METTL3 silencing reduced ACSL4 expression and suppressed hypoxia-induced ferroptosis in trophoblasts, and ACSL4 re-expression partially reversed the protective effects, providing rescue evidence for a causal contribution. The review nonetheless cautions that the clinical placental data are primarily marker-based and do not by themselves establish trophoblast ferroptotic cell death.

The remaining isoforms fare far less well in this assessment. ACSL3 is a candidate metabolic node whose anti-ferroptotic role, established through activation of monounsaturated fatty acids such as oleate in non-reproductive systems, has never been directly validated in any female reproductive disease; in cervical cancer, the demonstrated HPV/IGF2BP3/SCD pathway increases oleic acid production but ACSL3 itself was not measured. ACSL5 has disease-specific expression evidence in endometriosis, where single-cell RNA sequencing showed upregulation in endothelial cells of ectopic lesions, and a transcriptomic association with lymph-node metastasis prediction in cervical cancer, but no direct functional validation anywhere in the field. ACSL6 has no direct evidence among the six disorders reviewed, with only associative genetic links to premature ovarian failure, although in colorectal and breast cancer models ACSL6 overexpression enhanced DHA-induced lipid peroxidation and ferroptosis in a ferrostatin-1-reversible manner.

Looking forward, the review argues that the field’s priority should shift from expanding associative gene signatures toward causal, cell-type-resolved validation. Single-cell and spatial transcriptomics can identify which cells produce each isoform, targeted lipidomics and stable-isotope tracing can determine how each enzyme redirects fatty acid flux, and isoform-specific genetic perturbation in primary cells, patient-derived organoids, and trophoblast models can test mechanism directly. Translation also faces pharmacological hurdles: selective inhibitors exist for ACSL1 and, more recently, ACSL4, but tools remain limited across the family, and because ACSLs participate in physiological fatty acid activation, systemic inhibition risks perturbing normal lipid homeostasis. The authors conclude that immediate clinical inhibition of the ACSL family is premature, and that rigorous validation of disease-specific ACSL dependencies must come first, particularly in non-malignant reproductive disorders and pregnancy, where the safety of any ACSL-directed intervention has not been established.

Subject of Research: Isoform-specific roles of long-chain acyl-CoA synthetases in lipid metabolism, ferroptosis, and inflammatory signaling across female reproductive diseases

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

Article References: Jin, S., Guo, L., Wu, Z., Wang, Z., Liu, R., Kong, Y., & Zhang, H. (2026). Long-chain acyl-CoA synthetases in female reproductive diseases: isoform-specific regulation of lipid metabolism, ferroptosis, and inflammatory signaling. Frontiers in Endocrinology, 17, Article 1967984. https://doi.org/10.3389/fendo.2026.1967984

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1967984

Keywords: ACSL4, ferroptosis, lipid metabolism, ovarian cancer, endometrial cancer, polycystic ovary syndrome, endometriosis, preeclampsia, cervical cancer, fatty acid oxidation, polyunsaturated fatty acids, inflammatory signaling