Long-chain acyl-CoA synthetases in female reproductive diseases: isoform-specific regulation of lipid metabolism, ferroptosis, and inflammatory signaling
4 affiliations
- 1Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University
- 2Advanced Institute for Medical Sciences, Dalian Medical University
- 3Department of Otorhinolaryngology, the Second Hospital of Dalian Medical University
- 4School of Basic Medical Sciences, Dalian University of Technology
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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BibTeX
@article{jin2026longchain,
title = {{Long-chain acyl-CoA synthetases in female reproductive diseases: isoform-specific regulation of lipid metabolism, ferroptosis, and inflammatory signaling}},
author = {Shanyuan Jin and Lin Guo and Zishuo Wu and Zirong Wang and Runyuan Liu and Ying Kong and Hongshuo Zhang},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1967984},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1967984/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Long-chain acyl-CoA synthetases in female reproductive diseases: isoform-specific regulation of lipid metabolism, ferroptosis, and inflammatory signaling
AU - Shanyuan Jin
AU - Lin Guo
AU - Zishuo Wu
AU - Zirong Wang
AU - Runyuan Liu
AU - Ying Kong
AU - Hongshuo Zhang
PY - 2026
DA - 2026/10/28
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1967984
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1967984/full
AB - 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.
SN - 1664-2392
ER -