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Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review)

  • Authors:
    • Shenghui Ge
    • Deyue Kong
    • Shuyue Fan
    • Yi Luo
    • Xiao Yin
    • Zehua Jin
    • Wenqing Xia
    • Jianhua Ma
  • View Affiliations / Copyright

    Affiliations: Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210012, P.R. China
    Copyright: © Ge et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 54
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    Published online on: December 30, 2025
       https://doi.org/10.3892/ijmm.2025.5725
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Abstract

Cognitive impairment remains an important global health concern, with the molecular mechanisms regulating its progression being a primary research focus. Ferroptosis, a unique form of programmed cell death characterized by iron‑dependent lipid peroxidation, has been increasingly recognized for its essential role in the progression of various neurodegenerative diseases and diabetes‑associated cognitive impairment. The present review summarizes current evidence on how ferroptosis contributes to cognitive decline and outlines its regulation through lipid, iron and glutathione metabolism; it further discusses how diverse upstream pathologies converge on ferroptosis as a shared mechanism underlying cognitive dysfunction. In addition, recent advances in ferroptosis‑related biomarkers and therapeutic strategies are highlighted, with the aim of providing a clearer framework for understanding its pathogenic roles and guiding future clinical translation.
View Figures

Figure 1

Core molecular mechanism of
ferroptosis. ACSL4, acyl-CoA synthetase long-chain family member 4;
DMT1, divalent metal transporter 1; GPX4, glutathione peroxidase 4;
GSH, glutathione; GSSG, oxidized glutathione; LIP, labile iron
pool; LPCAT3, lysophosphatidylcholine acyltransferase 3; NCOA4,
nuclear receptor coactivator 4; PL-PUFAs, phospholipid-containing
PUFAs; PL-PUFA-OH, phospholipid PUFA alcohol; PL-PUFA-OOH,
phospholipid PUFA hydroperoxide; PUFAs, polyunsaturated fatty
acids; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute
carrier family 7 member 11; STEAP3, six-transmembrane epithelial
antigen of prostate 3; TF, transferrin; TFR1, transferrin receptor
1; CoQ, coenzyme Q10; DHODH, dihydroorotate dehydrogenase; FSP1,
ferroptosis suppressor protein 1.

Figure 2

Role and regulatory mechanisms of
ferroptosis in AD. The regulation of ferroptosis can impact AD
through multiple mechanisms, including regulation of GSH levels,
Fenton reaction, Aβ, lipid metabolism, iron metabolism and the NRF2
signaling pathway. AD, Alzheimer's disease; ACSL4, acyl-CoA
synthetase long-chain family member 4; ATG7, autophagy related 7;
Aβ, amyloid-β; DMT1, divalent metal transporter 1; GPX4,
glutathione peroxidase 4; GSH, glutathione; GSSG, oxidized
glutathione; LIP, labile iron pool; LPCAT3, lysophosphatidylcholine
acyltransferase 3; NAC, N-acetylcysteine; NCOA4, nuclear receptor
coactivator 4; NRF2, nuclear factor erythroid 2-related factor 2;
PL-PUFAs, phospholipid-containing PUFAs; PL-PUFA-OH, phospholipid
PUFA alcohol; PL-PUFA-OOH, phospholipid PUFA hydroperoxide; PUFAs,
polyunsaturated fatty acids; ROS, reactive oxygen species; RSL3,
RAS-selective lethal 3; SLC3A2, solute carrier family 3 member 2;
SLC7A11, solute carrier family 7 member 11; STEAP3,
six-transmembrane epithelial antigen of prostate 3; TF,
transferrin; TFR1, transferrin receptor 1; UPR, unfolded protein
response.

Figure 3

Role and regulatory mechanisms of
ferroptosis in PD. Ferroptosis in PD is regulated by multiple
interconnected pathways, including the GPX4/GSH system, iron and
lipid metabolism, the NRF2 signaling pathway, and mitochondrial
function. ACSL4, acyl-CoA synthetase long-chain family member 4;
AKT, protein kinase B; BAP1, BRCA1 associated protein 1; CR3,
complement receptor 3; DMT1, divalent metal transporter 1; DPP4,
dipeptidyl peptidase-4; FTO, FTO α-ketoglutarate dependent
dioxygenase; GABA, γ-aminobutyric acid; GPX4, glutathione
peroxidase 4; GSH, glutathione; GSSG, oxidized glutathione; GSK3β,
glycogen synthase kinase 3β; KEAP1, kelch-like ECH-associated
protein 1; LIP, labile iron pool; LPCAT3, lysophosphatidylcholine
acyltransferase 3; LRRK2, leucine-rich repeat kinase 2; MT1,
melatonin receptor 1; NCOA4, nuclear receptor coactivator 4; NRF2,
nuclear factor erythroid 2-related factor 2; NOX, NADPH oxidase;
PD, Parkinson's disease; PL-PUFAs, phospholipid-containing PUFAs;
PL-PUFA-OH, phospholipid PUFA alcohol; PL-PUFA-OOH, phospholipid
PUFA hydroperoxide; PUFAs, polyunsaturated fatty acids; ROS,
reactive oxygen species; SLC3A2, solute carrier family 3 member 2;
SLC7A11, solute carrier family 7 member 11; STEAP3,
six-transmembrane epithelial antigen of prostate 3; TF,
transferrin; TFR1, transferrin receptor 1.

Figure 4

Role and regulatory mechanisms of
ferroptosis in DACI. The regulation of ferroptosis can impact DACI
through multiple mechanisms, including the modulation of the
GPX4/GSH system, iron and ROS metabolism, mitochondrial homeostasis
and the NRF2 and PERK signaling pathways. ACSL4, acyl-CoA
synthetase long-chain family member 4; AMPK, AMP-activated protein
kinase; Cav-1, caveolin-1; DACI, diabetes-associated cognitive
impairment; DMT1, divalent metal transporter 1; GPX4, glutathione
peroxidase 4; GSH, glutathione; GSSG, oxidized glutathione; LIP,
labile iron pool; LPCAT3, lysophosphatidylcholine acyltransferase
3; NCOA4, nuclear receptor coactivator 4; PERK, PKR-like
endoplasmic reticulum kinase; PL-PUFAs, phospholipid-containing
PUFAs; PL-PUFA-OH, phospholipid PUFA alcohol; PL-PUFA-OOH,
phospholipid PUFA hydroperoxide; PUFAs, polyunsaturated fatty
acids; ROS, reactive oxygen species; SLC3A2, solute carrier family
3 member 2; SLC7A11, solute carrier family 7 member 11; SLC40A1,
solute carrier family 40 member 1; STEAP3, six-transmembrane
epithelial antigen of prostate 3; TF, transferrin; TFR1,
transferrin receptor 1; TREM1, triggering receptor expressed on
myeloid cells 1.

Figure 5

Clinical workflow for ferroptosis
biomarkers in cognitive impairment diagnosis. MoCA, Montreal
Cognitive Assessment; MMSE, Mini-Mental State Examination; T2DM,
type 2 diabetes mellitus; CSF, cerebrospinal fluid; MDA,
malondialdehyde; 4-HNE, 4-hydroxynonenal; GPX4, glutathione
peroxidase 4; GSH/GSSG, reduced/oxidized glutathione ratio; qSM,
quantitative susceptibility mapping; AD, Alzheimer's disease; PD,
Parkinson's disease; DACI, diabetes-associated cognitive
impairment; FRG, ferroptosis-related gene; TFRC, transferrin
receptor; SLC7A11, solute carrier family 7 member 11.
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Copy and paste a formatted citation
Spandidos Publications style
Ge S, Kong D, Fan S, Luo Y, Yin X, Jin Z, Xia W and Ma J: Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review). Int J Mol Med 57: 54, 2026.
APA
Ge, S., Kong, D., Fan, S., Luo, Y., Yin, X., Jin, Z. ... Ma, J. (2026). Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review). International Journal of Molecular Medicine, 57, 54. https://doi.org/10.3892/ijmm.2025.5725
MLA
Ge, S., Kong, D., Fan, S., Luo, Y., Yin, X., Jin, Z., Xia, W., Ma, J."Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review)". International Journal of Molecular Medicine 57.3 (2026): 54.
Chicago
Ge, S., Kong, D., Fan, S., Luo, Y., Yin, X., Jin, Z., Xia, W., Ma, J."Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review)". International Journal of Molecular Medicine 57, no. 3 (2026): 54. https://doi.org/10.3892/ijmm.2025.5725
Copy and paste a formatted citation
x
Spandidos Publications style
Ge S, Kong D, Fan S, Luo Y, Yin X, Jin Z, Xia W and Ma J: Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review). Int J Mol Med 57: 54, 2026.
APA
Ge, S., Kong, D., Fan, S., Luo, Y., Yin, X., Jin, Z. ... Ma, J. (2026). Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review). International Journal of Molecular Medicine, 57, 54. https://doi.org/10.3892/ijmm.2025.5725
MLA
Ge, S., Kong, D., Fan, S., Luo, Y., Yin, X., Jin, Z., Xia, W., Ma, J."Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review)". International Journal of Molecular Medicine 57.3 (2026): 54.
Chicago
Ge, S., Kong, D., Fan, S., Luo, Y., Yin, X., Jin, Z., Xia, W., Ma, J."Role and mechanisms of ferroptosis in cognitive impairment: From molecular pathways to therapeutic targets (Review)". International Journal of Molecular Medicine 57, no. 3 (2026): 54. https://doi.org/10.3892/ijmm.2025.5725
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