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Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review)

  • Authors:
    • Di Cheng
    • Songbin Yang
    • Cuilan Wang
    • Kefeng Fan
    • Fengchun Gao
    • Qian Sun
  • View Affiliations / Copyright

    Affiliations: Department of Obstetrics, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250000, P.R. China
    Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 121
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    Published online on: March 12, 2026
       https://doi.org/10.3892/ijmm.2026.5792
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Abstract

Fetal growth restriction (FGR) is strongly associated with adverse perinatal outcomes, and placental oxidative stress has been identified as a central pathological mechanism. In maternal plasma, cord blood and placental tissues from FGR pregnancies, the levels of malondialdehyde, 4‑hydroxynonenal, reactive oxygen metabolites and 8‑hydroxy‑2'‑deoxyguanosine are consistently elevated. In parallel, superoxide dismutase and glutathione peroxidase show compensatory upregulation, while catalase activity declines, reflecting increased oxidative burden coupled with impaired antioxidant defense. Major sources of reactive oxygen species include NADPH oxidase and xanthine oxidase, mitochondrial electron transport and ischemia‑reperfusion events. Mechanistic evidence further indicates that oxidative stress interacts with endoplasmic reticulum stress, metabolic reprogramming and epigenetic alterations, thereby aggravating trophoblast dysfunction and placental vascular injury. Aberrant DNA hypomethylation, histone modifications and dysregulation of noncoding RNAs, such as microRNA (miR)‑199a, miR‑210‑3p and miR‑21, contribute to persistent remodeling of trophoblast behavior and vascular networks. Early clinical studies have suggested that melatonin and pentoxifylline may alleviate placental oxidative injury and improve selected perinatal outcomes, whereas vitamin C and E supplementation shows no clear benefit. Preclinical investigations have highlighted the potential of mitochondria‑targeted and classical antioxidants, including mitoquinone mesylate, N‑acetylcysteine, tempol and resveratrol; however, their efficacy and safety appear to be dependent on gestational timing and dosage. Further well-designed clinical trials are warranted to establish effective antioxidant‑based strategies for FGR.
View Figures

Figure 1

Major sources of ROS and their
molecular roles in the pathogenesis of FGR. ROS are mainly
generated from three sources: Enzyme-derived ROS, mitochondrial ROS
and I/R-induced ROS. Enzyme-derived ROS are mainly produced by NOX
and xanthine oxidase, while mitochondrial ROS mainly result from
electron leakage at complexes I and III of the electron transport
chain. During I/R, RET occurs at complex I. ER stress regulates
cell apoptosis and autophagy via the IRE1α, PERK and ATF6 signaling
pathways, thereby contributing to the progression of FGR. In FGR,
glucose uptake is reduced, the mitochondrial structure is
disrupted, and the TCA cycle is impaired, ultimately resulting in
decreased ATP production. Furthermore, epigenetic regulation also
serves a key role in FGR. The placenta of growth-restricted fetuses
exhibits global hypomethylation in hypoxia-related pathways,
accompanied by marked upregulation of mitochondrial lncRNAs.
Several miRNAs, including miR-199a-5p, miR-155, miR-16, miR-29b,
miR-204, miR-1 and miR-21, are also implicated in placental
development and are dynamically regulated by oxidative stress. ROS,
reactive oxygen species; I/R, ischemia-reperfusion; NOX, NADPH
oxidase; RET, reverse electron transport; ER, endoplasmic
reticulum; FGR, fetal growth restriction; TCA, tricarboxylic acid;
lncRNA/lnc, long noncoding RNA; miRNA/miR, microRNA; PERK, protein
kinase RNA-like endoplasmic reticulum kinase; ATF6, activating
transcription factor 6; IRE1α, inositol-requiring enzyme 1α; Glc,
glucose.

Figure 2

Major sources and molecular
mechanisms of ROS generation. NOX is a major source of
O2•−, and elevated O2•−
levels are associated with activation of the p38 MAPK pathway. The
NOX subunits p22phox, p47phox and
p67phox are highly expressed in the placenta. Excess
H2O2 can be further converted into •OH via
the Fenton reaction. XO catalyzes the stepwise oxidation of
hypoxanthine to xanthine and uric acid, accompanied by the
generation of H2O2 and O2. The
electron transport chain, consisting of five multi-subunit protein
complexes (I-V), resides in the mitochondrial inner membrane.
Complexes I, III and IV pump protons (H+) from the
mitochondrial matrix into the intermembrane space. During oxidative
phosphorylation, O2 undergoes partial reduction by
electrons leaking from complexes I and III, giving rise to
O2•−. In the matrix,
O2•− is dismutated to
H2O2. H2O2 may
subsequently undergo the Fenton reaction with
Fe2+/Cu+ to produce •OH. During reperfusion,
the TCA cycle intermediate succinate selectively accumulates. The
accumulated succinate is rapidly re-oxidized by succinate
dehydrogenase, driving reverse electron transport at complex I and
triggering a burst of ROS. Ischemia-reperfusion also facilitates
the conversion of xanthine dehydrogenase to XO, which in its
oxidase form uses O2 as an electron acceptor to
continuously generate oxygen radicals. Increased FSS further
induces NOX4 expression, thereby enhancing
H2O2 production. NOX, NADPH oxidase; XO,
xanthine oxidase; TCA, tricarboxylic acid cycle; ROS, reactive
oxygen species; FSS, fluid shear stress; phox, phagocyte oxidase;
FAD, flavin adenine dinucleotide.

Figure 3

Oxidative stress and ROS signaling in
ER stress and the UPR. The ER is highly sensitive to oxidative
stress. When redox imbalance leads to the accumulation of misfolded
proteins within the ER lumen, it triggers ER stress and activates
the UPR. Under homeostatic conditions, the three major signaling
branches of the UPR (PERK, ATF6 and IRE1α) remain inactive through
their interaction with the molecular chaperone GRP78 at their
luminal domains. Upon stress induction, GRP78 dissociates from
these sensors, facilitating the oligomerization and
autophosphorylation of PERK, the translocation and cleavage of
ATF6, and the activation of IRE1α. Activated PERK phosphorylates
the transcription factor NRF2, leading to its release from the
Keap1 complex and the subsequent induction of antioxidant gene
expression. PERK also phosphorylates the translation initiation
factor eIF2α, thereby globally inhibiting protein synthesis while
selectively enhancing the translation of ATF4. ATF4 regulates a
series of cell fate-related genes, including CHOP, GADD34, ATF3 and
ATGs. Upon CHOP upregulation, GADD34-mediated dephosphorylation of
eIF2α restores translation initiation. CHOP also induces the
expression of the ER oxidoreductase ERO1α, which triggers the
release of cytochrome c and activates the caspase-dependent
apoptotic signaling pathway. In addition, CHOP can
transcriptionally downregulate Bcl-2 and upregulate Bim, further
promoting apoptosis through multiple mechanisms. ATF6 is
transported to the Golgi apparatus, where it is cleaved by SP1 and
SP2 proteases to release its N-terminal transcriptionally active
fragment. This fragment enters the nucleus and binds to
cis-regulatory elements such as CRE and ERSE, inducing the
transcription of chaperone proteins, including GRP78 and GRP94, as
well as cell fate regulators such as CHOP. The activation of IRE1α
also depends on oligomerization and autophosphorylation. Its
ribonuclease activity then mediates the splicing of XBP1 mRNA,
generating the active XBP1s protein, which enhances the expression
of ERAD components and molecular chaperones. However, under
prolonged stress conditions, IRE1α recruits TRAF2, leading to the
activation of ASK1 and subsequent stimulation of the p38 MAPK and
JNK signaling cascades. ROS, reactive oxygen species; ER,
endoplasmic reticulum; UPR, unfolded protein response; PERK,
PKR-like endoplasmic reticulum kinase; ATF, activating
transcription factor; IRE1α, inositol-requiring enzyme 1α; GRP78,
glucose-regulated protein 78; NRF2, nuclear factor erythroid
2–related factor 2; Keap1, Kelch-like ECH-associated protein 1;
eIF2α, eukaryotic initiation factor 2α; CHOP, C/EBP homologous
protein; GADD34, growth arrest and DNA damage-inducible protein 34;
ATGs, autophagy-related genes; ERO1α, endoplasmic reticulum
oxidoreductin 1α; SP1, site-1 protease; SP2, site-2 protease; CRE,
cAMP response element; ERSE, ER stress response element; GRP94,
glucose-regulated protein 94; XBP1, X-box binding protein 1; XBP1s,
spliced X-box binding protein 1; ERAD, endoplasmic
reticulum-associated degradation; TRAF2, TNF receptor-associated
factor 2; ASK1, apoptosis signal-regulating kinase 1; P, phosphate
group; ATF6f, activating transcription factor 6 fragment; XBP1u,
X-box binding protein 1 (unspliced); Bim, Bcl-2 interacting
mediator of cell death.

Figure 4

ROS accumulation, mitochondrial
dysfunction and metabolic reprogramming in FGR and maternal
nutritional models across multiple tissues. In the liver, the
spontaneous FGR pig model shows that neonatal piglets exhibit
elevated levels of α1-acid glycoprotein and electron
transport chain complex IV. In maternal caloric restriction
experiments in rats, a reduction in maternal energy intake led to
an increase in the lipid peroxidation marker 4-hydroxynonenal.
Post-weaning catch-up growth reduced the expression of
mitochondrial DNA-encoded genes. In the pancreas, FGR offspring
exhibit impaired β-cell function and insufficient insulin
secretion. Their islet ROS levels increase with age, accompanied by
decreased activities of citrate synthase and complexes I and III.
In skeletal muscle, early adult FGR offspring display reduced
insulin-stimulated glucose uptake and glycogen synthesis. Maternal
caloric restriction experiments similarly demonstrate that the
mitochondrial number and content are reduced, accompanied by
decreased coupled and uncoupled respiration, fatty acid oxidation,
and complex I function. In the heart, prenatal nicotine exposure
decreases cardiac PDI levels, and PDI deficiency further induces
mitochondrial dysfunction and oxidative injury, manifested as
reduced protein levels of SOD2 and mitochondrial complexes I, II,
IV and V. FGR, fetal growth restriction; PDI, protein disulfide
isomerase; ROS, reactive oxygen species; p66Shc, p66 Src homology 2
domain-containing transforming protein C; SOD2, superoxide
dismutase 2.
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Copy and paste a formatted citation
Spandidos Publications style
Cheng D, Yang S, Wang C, Fan K, Gao F and Sun Q: Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review). Int J Mol Med 57: 121, 2026.
APA
Cheng, D., Yang, S., Wang, C., Fan, K., Gao, F., & Sun, Q. (2026). Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review). International Journal of Molecular Medicine, 57, 121. https://doi.org/10.3892/ijmm.2026.5792
MLA
Cheng, D., Yang, S., Wang, C., Fan, K., Gao, F., Sun, Q."Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review)". International Journal of Molecular Medicine 57.5 (2026): 121.
Chicago
Cheng, D., Yang, S., Wang, C., Fan, K., Gao, F., Sun, Q."Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 121. https://doi.org/10.3892/ijmm.2026.5792
Copy and paste a formatted citation
x
Spandidos Publications style
Cheng D, Yang S, Wang C, Fan K, Gao F and Sun Q: Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review). Int J Mol Med 57: 121, 2026.
APA
Cheng, D., Yang, S., Wang, C., Fan, K., Gao, F., & Sun, Q. (2026). Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review). International Journal of Molecular Medicine, 57, 121. https://doi.org/10.3892/ijmm.2026.5792
MLA
Cheng, D., Yang, S., Wang, C., Fan, K., Gao, F., Sun, Q."Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review)". International Journal of Molecular Medicine 57.5 (2026): 121.
Chicago
Cheng, D., Yang, S., Wang, C., Fan, K., Gao, F., Sun, Q."Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 121. https://doi.org/10.3892/ijmm.2026.5792
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