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Luteolin in Safflower Leaves Suppresses Microglial Inflammation Through FOXO3-Mediated Trem2 Transcription
Tiantian Zhang, Shuangxi Zhang, Jiayang Ma, Dmitrii Atiakshin, Shujun Han, Mami Noda, Midori Hiramatsu, Jiankang Liu et al.. Antioxidants (Basel, Switzerland), 2025-12-12
Topic: Inflammation, microglia and astrocytes
Neuroinflammation driven by microglial activation is a hallmark of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial inflammation, yet strategies to modulate its expression remain limited. Safflower leaves, a vegetable rich in flavonoids-particularly luteolin-were previously shown to attenuate neuroinflammation, reduce oxidative stress, and ameliorate cognitive impairment in APP/PS1 mice. Here, we demonstrated that safflower leaves inhibit microglial inflammation and upregulate TREM2 in APP/PS1 mice. Luteolin, the major active flavonoid in safflower leaves, exerted anti-inflammatory effects in lipopolysaccharides (LPS)-activated microglia. Mechanistically, luteolin enhanced Trem2 transcription by activating forkhead box protein O3 (FOXO3), a novel transcriptional regulator of Trem2 identified through promoter analysis. FOXO3 binding to the Trem2 promoter was essential for this regulation, and luteolin further promoted FOXO3 nuclear translocation. Crucially, Trem2 knockdown attenuated luteolin's anti-inflammatory effects, confirming TREM2 as a key mediator. Overall, our study reveals the FOXO3-TREM2 axis as a potential therapeutic target for neuroinflammation and highlights luteolin present in safflower leaves as a candidate dietary intervention for AD, providing new mechanistic insights into the anti-inflammatory activity of this natural antioxidant.
Key findings
- Here, we demonstrated that safflower leaves inhibit microglial inflammation and upregulate TREM2 in APP/PS1 mice.
- Overall, our study reveals the FOXO3-TREM2 axis as a potential therapeutic target for neuroinflammation and highlights luteolin present in safflower leaves as a candidate dietary intervention for AD, providing new mechanistic insights into the anti-inflammatory activity of this natural antioxidant.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Antioxidants (Basel, Switzerland)) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41462694) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Zhang, T., Zhang, S., Ma, J., Atiakshin, D., Han, S., Noda, M., et al. (2025). Luteolin in Safflower Leaves Suppresses Microglial Inflammation Through FOXO3-Mediated Trem2 Transcription. Antioxidants (Basel, Switzerland). https://doi.org/10.3390/antiox14121495
Vancouver
Zhang T, Zhang S, Ma J, Atiakshin D, Han S, Noda M, et al. Luteolin in Safflower Leaves Suppresses Microglial Inflammation Through FOXO3-Mediated Trem2 Transcription. Antioxidants (Basel, Switzerland). 2025. doi:10.3390/antiox14121495. PMID: 41462694.
BibTeX
@article{zhang2025-41462694,
author = {Zhang, Tiantian and Zhang, Shuangxi and Ma, Jiayang and Atiakshin, Dmitrii and Han, Shujun and Noda, Mami and Hiramatsu, Midori and Liu, Jiankang and others},
title = {{Luteolin in Safflower Leaves Suppresses Microglial Inflammation Through FOXO3-Mediated Trem2 Transcription}},
journal = {Antioxidants (Basel, Switzerland)},
year = {2025},
doi = {10.3390/antiox14121495},
pmid = {41462694},
url = {https://doi.org/10.3390/antiox14121495}
}
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