Fenchone attenuates CD68-dependent 7-ketocholesterol accumulation, cholesterol dyshomeostasis and inflammatory responses via modulation of macrophage polarization

doi:10.1007/s10787-025-01836-5

. 2025 Jul 1.

doi: 10.1007/s10787-025-01836-5. Online ahead of print.

Fenchone attenuates CD68-dependent 7-ketocholesterol accumulation, cholesterol dyshomeostasis and inflammatory responses via modulation of macrophage polarization

Sangeetha Ravi¹, Livya Catherene Martin¹, Manikandan Kumaresan¹, Jaya Suriya Mani¹, Beulaja Manikandan¹, Manikandan Ramar²

Affiliations

¹ Department of Zoology, University of Madras, Guindy Campus, Chennai, 600 025, India.
² Department of Zoology, University of Madras, Guindy Campus, Chennai, 600 025, India. manikandanramar@yahoo.co.in.

PMID: 40591211
DOI: 10.1007/s10787-025-01836-5

Fenchone attenuates CD68-dependent 7-ketocholesterol accumulation, cholesterol dyshomeostasis and inflammatory responses via modulation of macrophage polarization

Sangeetha Ravi et al. Inflammopharmacology. 2025.

. 2025 Jul 1.

doi: 10.1007/s10787-025-01836-5. Online ahead of print.

Authors

Sangeetha Ravi¹, Livya Catherene Martin¹, Manikandan Kumaresan¹, Jaya Suriya Mani¹, Beulaja Manikandan¹, Manikandan Ramar²

Affiliations

¹ Department of Zoology, University of Madras, Guindy Campus, Chennai, 600 025, India.
² Department of Zoology, University of Madras, Guindy Campus, Chennai, 600 025, India. manikandanramar@yahoo.co.in.

PMID: 40591211
DOI: 10.1007/s10787-025-01836-5

Abstract

Background: Foam cell formation, driven by oxidized low-density lipoprotein (Ox-LDL) uptake, particularly 7-ketocholesterol (7KCh), is a pivotal event in lipid-associated inflammatory diseases such as atherosclerosis. Conventional therapies often yield side effects, prompting interest in plant-derived biomolecules. Fenchone, a monoterpene from Foeniculum vulgare, has recently garnered attention for its anti-inflammatory and anti-lipidemic potential.

Purpose: This study elucidates the pharmacologic efficacy of fenchone in mitigating foam cell formation by modulating cholesterol homeostasis, inflammatory signaling and polarization in macrophages.

Methods: Murine IC-21 macrophages were induced with 7KCh and co-treated with fenchone. Cell viability was assessed using alamar blue assay, while lipid and calcium accumulation were analyzed with oil red O and alizarin red S staining. Pinocytosis, phagocytosis and actin cytoskeleton were evaluated with neutral red, goat RBCs uptake and phalloidin, respectively. Molecular changes were determined using ELISA, flow cytometry, PCR, western blot and in silico docking.

Results: Fenchone significantly inhibited lipid and calcium accumulation, reduced lipid peroxidation and restored homeostatic endocytosis with anti-inflammatory cytoskeleton. It enhanced anti-inflammatory TGFβ1 and Smad2/3 while suppressing pro-inflammatory NF-κB, IL-1β, IL-6 and TNF-α. In addition, fenchone regulated cholesterol homeostasis via ABCA1, ApoE, LXR, CD36 and promoted M2 polarization by increasing CD163 and CD206 markers, downregulating M1 markers (CD38, CD68 and CD86). Computational analysis indicated the interactive affinity of 7KCh toward the CD68 scavenger receptor, which was prevented by fenchone.

Conclusion: These findings highlight the therapeutic potential of fenchone in managing atherosclerosis by targeting CD68-mediated 7KCh uptake and inflammatory cascade, thereby emerging as a potential pharmacotherapeutic agent in inflammatory diseases.

Keywords: 7-ketocholesterol; Fenchone; Inflammation; Lipids; Macrophage.

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Conflict of interest statement

Declarations. Conflict of interest statement: The authors declare no conflict of interest.

References

1. Ahmad W, Ansari MA, Yusuf M, Amir M, Wahab S, Alam P, Alomary MN, Alhuwayri AA, Khan M, Ali A, Warsi MH (2022) Antibacterial, anticandidal, and antibiofilm potential of fenchone: in vitro, molecular docking and in silico/ADMET study. Plants 11(18):2395. https://doi.org/10.3390/plants11182395 - DOI - PubMed - PMC
1. Anderson A, Campo A, Fulton E, Corwin A, Jerome WG III, O’Connor MS (2020) 7-Ketocholesterol in disease and aging. Redox Biol 29:101380. https://doi.org/10.1016/j.redox.2019.101380 - DOI - PubMed
1. Araruna ME, Júnior EB, Serafim CA, Pessoa MM, Pessôa ML, Alves VP, Silva MS, Sobral MV, Alves AF, Nunes MK, Araújo AA (2024) (-)-Fenchone Prevents cysteamine-induced duodenal ulcers and accelerates healing promoting re-epithelialization of gastric ulcers in rats via antioxidant and immunomodulatory mechanisms. Pharmaceuticals 17(5):641. https://doi.org/10.3390/ph17050641 - DOI - PubMed - PMC
1. Azadpour M, Farajollahi MM, Dariushnejad H, Varzi AM, Varezardi A, Barati M (2021) Effects of synthetic silymarin-PLGA nanoparticles on M2 polarization and inflammatory cytokines in LPS-treated murine peritoneal macrophages. Iran J Basic Med Sci 24(10):1446. https://doi.org/10.22038/IJBMS.2021.59312.13161
1. Bai J, Zhang X, Meng W, Xu H, Liu Y, Zhong Y, Lin X, Wang J, Lv G, Gu Y (2024) Dioscin decreases M2 polarization via inhibiting a positive feedback loop between RBM47 and NF-κB in glioma. Phytomedicine 128:155417. https://doi.org/10.1016/j.phymed.2024.155417 - DOI - PubMed

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[1] Ahmad W, Ansari MA, Yusuf M, Amir M, Wahab S, Alam P, Alomary MN, Alhuwayri AA, Khan M, Ali A, Warsi MH (2022) Antibacterial, anticandidal, and antibiofilm potential of fenchone: in vitro, molecular docking and in silico/ADMET study. Plants 11(18):2395. https://doi.org/10.3390/plants11182395 - DOI - PubMed - PMC

[2] Ahmad W, Ansari MA, Yusuf M, Amir M, Wahab S, Alam P, Alomary MN, Alhuwayri AA, Khan M, Ali A, Warsi MH (2022) Antibacterial, anticandidal, and antibiofilm potential of fenchone: in vitro, molecular docking and in silico/ADMET study. Plants 11(18):2395. https://doi.org/10.3390/plants11182395 - DOI - PubMed - PMC

[3] Anderson A, Campo A, Fulton E, Corwin A, Jerome WG III, O’Connor MS (2020) 7-Ketocholesterol in disease and aging. Redox Biol 29:101380. https://doi.org/10.1016/j.redox.2019.101380 - DOI - PubMed

[4] Anderson A, Campo A, Fulton E, Corwin A, Jerome WG III, O’Connor MS (2020) 7-Ketocholesterol in disease and aging. Redox Biol 29:101380. https://doi.org/10.1016/j.redox.2019.101380 - DOI - PubMed

[5] Araruna ME, Júnior EB, Serafim CA, Pessoa MM, Pessôa ML, Alves VP, Silva MS, Sobral MV, Alves AF, Nunes MK, Araújo AA (2024) (-)-Fenchone Prevents cysteamine-induced duodenal ulcers and accelerates healing promoting re-epithelialization of gastric ulcers in rats via antioxidant and immunomodulatory mechanisms. Pharmaceuticals 17(5):641. https://doi.org/10.3390/ph17050641 - DOI - PubMed - PMC

[6] Araruna ME, Júnior EB, Serafim CA, Pessoa MM, Pessôa ML, Alves VP, Silva MS, Sobral MV, Alves AF, Nunes MK, Araújo AA (2024) (-)-Fenchone Prevents cysteamine-induced duodenal ulcers and accelerates healing promoting re-epithelialization of gastric ulcers in rats via antioxidant and immunomodulatory mechanisms. Pharmaceuticals 17(5):641. https://doi.org/10.3390/ph17050641 - DOI - PubMed - PMC

[7] Azadpour M, Farajollahi MM, Dariushnejad H, Varzi AM, Varezardi A, Barati M (2021) Effects of synthetic silymarin-PLGA nanoparticles on M2 polarization and inflammatory cytokines in LPS-treated murine peritoneal macrophages. Iran J Basic Med Sci 24(10):1446. https://doi.org/10.22038/IJBMS.2021.59312.13161

[8] Azadpour M, Farajollahi MM, Dariushnejad H, Varzi AM, Varezardi A, Barati M (2021) Effects of synthetic silymarin-PLGA nanoparticles on M2 polarization and inflammatory cytokines in LPS-treated murine peritoneal macrophages. Iran J Basic Med Sci 24(10):1446. https://doi.org/10.22038/IJBMS.2021.59312.13161

[9] Bai J, Zhang X, Meng W, Xu H, Liu Y, Zhong Y, Lin X, Wang J, Lv G, Gu Y (2024) Dioscin decreases M2 polarization via inhibiting a positive feedback loop between RBM47 and NF-κB in glioma. Phytomedicine 128:155417. https://doi.org/10.1016/j.phymed.2024.155417 - DOI - PubMed

[10] Bai J, Zhang X, Meng W, Xu H, Liu Y, Zhong Y, Lin X, Wang J, Lv G, Gu Y (2024) Dioscin decreases M2 polarization via inhibiting a positive feedback loop between RBM47 and NF-κB in glioma. Phytomedicine 128:155417. https://doi.org/10.1016/j.phymed.2024.155417 - DOI - PubMed

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Fenchone attenuates CD68-dependent 7-ketocholesterol accumulation, cholesterol dyshomeostasis and inflammatory responses via modulation of macrophage polarization

Affiliations

Fenchone attenuates CD68-dependent 7-ketocholesterol accumulation, cholesterol dyshomeostasis and inflammatory responses via modulation of macrophage polarization

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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Research Materials

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