# Macrophage migration inhibitory factor alleviates irradiation induced apoptosis of BMSCs through the LncRNA MEG3/NOX4 axis

**Authors:** Kai Hu, Han Zhou, Hongwei Hu, Zhibiao Bai, Lingwei Mou, Shaohao Wu, Zeyu Shou, Changbao Liu, Chun Chen

PMC · DOI: 10.1515/med-2025-1339 · Open Medicine · 2026-02-13

## TL;DR

This study shows how macrophage migration inhibitory factor (MIF) protects bone marrow stem cells from radiation damage.

## Contribution

The study identifies a new mechanism involving LncRNA MEG3 and NOX4 through which MIF reduces cell death caused by radiation.

## Key findings

- Irradiation increases apoptosis and upregulates MEG3 and NOX4 in BMSCs.
- MIF reduces apoptosis by downregulating MEG3 and NOX4 expression.
- Overexpression of MEG3 or NOX4 reverses the protective effect of MIF.

## Abstract

This study aimed to explore the mechanism by which exogenous macrophage migration inhibitory factor (MIF) reduces apoptosis of mouse bone marrow mesenchymal stem cells (BMSCs) induced by irradiation under high oxidative stress.

BMSCs were cultured and exposed to irradiation using a linear accelerator to establish a radiation damage model. Cell viability was detected by the CCK-8 assay. Apoptosis rate and intracellular reactive oxygen species (ROS) production were measured by flow cytometry and fluorescence microscopy. The expression levels of Long non-coding RNA (lncRNA) MEG3, NOX4, and apoptosis-related genes were detected by western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence.

The CCK-8 assay, western blot, and flow cytometry confirmed that irradiation effectively induced BMSCs apoptosis and upregulated the expression of lncRNA MEG3, which was positively correlated with NOX4 expression. Western blot, immunofluorescence, and RT-qPCR results demonstrated that MIF protected BMSCs from irradiation-induced apoptosis and downregulated the expression of MEG3 and NOX4. Furthermore, MEG3 siRNA was shown to reduce irradiation-induced apoptosis. Western blot and flow cytometry analyses revealed that overexpression of either NOX4 or MEG3 could reverse the protective effect of MIF.

LncRNA MEG3 is an important regulatory factor in irradiation-induced apoptosis. The mechanism by which MIF protects BMSCs from irradiation-induced apoptosis is likely mediated through the regulation of the LncRNA MEG3/NOX4 signaling pathway.

## Linked entities

- **Genes:** MEG3 (maternally expressed 3) [NCBI Gene 55384], NOX4 (NADPH oxidase 4) [NCBI Gene 50507]
- **Proteins:** MIF (macrophage migration inhibitory factor)
- **Species:** Mus musculus (taxon 10090)

## Full-text entities

- **Genes:** COX2 (cytochrome c oxidase subunit II) [NCBI Gene 17709], Anxa5 (annexin A5) [NCBI Gene 11747] {aka Anx5, CPB-I}, Actb (actin, beta) [NCBI Gene 11461] {aka Actx, E430023M04Rik, beta-actin}, Pten (phosphatase and tensin homolog) [NCBI Gene 50557] {aka MMAC1, Mmac, TEP1}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], Cdkn1a (cyclin dependent kinase inhibitor 1A) [NCBI Gene 12575] {aka CAP20, CDKI, CIP1, Cdkn1, P21, SDI1}, Mif (macrophage migration inhibitory factor (glycosylation-inhibiting factor)) [NCBI Gene 17319] {aka DER6, GIF, Glif}, Meg3 (maternally expressed 3) [NCBI Gene 500717] {aka Gtl2, RGD1566401}, Nox4 (NADPH oxidase 4) [NCBI Gene 50490], Casp3 (caspase 3) [NCBI Gene 12367] {aka A830040C14Rik, AC-3, CASP-3, CC3, CPP-32, CPP32}, Meg3 (maternally expressed 3) [NCBI Gene 17263] {aka 2900016C05Rik, 3110050O07Rik, 6330408G06Rik, D12Bwg1266e, Gtl2}, Bax (BCL2-associated X protein) [NCBI Gene 12028], Ccr5 (C-C motif chemokine receptor 5) [NCBI Gene 12774] {aka AM4-7, CD195, Cmkbr5}, Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa}, Cd274 (CD274 antigen) [NCBI Gene 60533] {aka A530045L16Rik, B7h1, Pdcd1l1, Pdcd1lg1, Pdl1}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, Bcl2 (B cell leukemia/lymphoma 2) [NCBI Gene 12043] {aka Bcl-2, C430015F12Rik, D630044D05Rik, D830018M01Rik}, Hmgb1 (high mobility group box 1) [NCBI Gene 25459] {aka Ac2-008, Hmg1}
- **Diseases:** pulmonary fibrosis (MESH:D011658), tumorigenesis (MESH:D063646), osteonecrosis of the femoral head (MESH:D000070603), hypoxic (MESH:D002534), radiation damage (MESH:D011832), brain tumors (MESH:D001932), chronic (MESH:D002908), hypoxia (MESH:D000860), ischemia (MESH:D007511), rhinosinusitis (MESH:D000092562), necrosis (MESH:D009336), necrotic fractures (MESH:D050723), inflammation (MESH:D007249), cardiac fibrosis (MESH:D005355), IR (MESH:C537629), knee osteoarthritis (MESH:D020370), avascular necrosis of the femoral head (MESH:D005271), benign prostatic hyperplasia (MESH:D011470), emphysema (MESH:D004646), microangiopathy (MESH:D014652), cerebral ischemia (MESH:D002545), diabetes (MESH:D003920), osteonecrosis (MESH:D010020), cancer (MESH:D009369), uterine cancer (MESH:D014594)
- **Chemicals:** DCFH-DA (MESH:C029569), paraformaldehyde (MESH:C003043), CCK-8 (MESH:D012844), CO2 (MESH:D002245), BCA (MESH:C047117), Glutamax (MESH:C054122), DAPI (MESH:C007293), ROS (MESH:D017382), SDS (MESH:D012967), PVDF (MESH:C024865), PI (MESH:D010716), CCK- (MESH:D002766), penicillin (MESH:D010406), oxygen (MESH:D010100), Fenofibrate (MESH:D011345), DCFH (-), Triton X-100 (MESH:D017830), streptomycin (MESH:D013307), nicotine (MESH:D009538), Hoechst33342 (MESH:C017807)
- **Species:** Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090]
- **Cell lines:** C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU)

## Full text

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## Figures

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## References

50 references — full list in the complete paper: https://tomesphere.com/paper/PMC12919720/full.md

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Source: https://tomesphere.com/paper/PMC12919720