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Article

HSP90 Inhibition Disrupts 27-Hydroxycholesterol-Induced Inflammatory Signaling in Monocytic Cells

1
Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
2
Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
3
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, 17177 Stockholm, Sweden
4
School of Biomedical Convergence Engineering, Pusan National University, Yangsan 50612, Republic of Korea
5
Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
6
Transplantation Research Center, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(20), 9963; https://doi.org/10.3390/ijms26209963 (registering DOI)
Submission received: 22 August 2025 / Revised: 4 October 2025 / Accepted: 9 October 2025 / Published: 13 October 2025
(This article belongs to the Special Issue Dialogue Between Inflammation and Immunity: From Mechanism to Therapy)

Abstract

27-Hydroxycholesterol (27OHChol), a cholesterol metabolite, induces inflammatory responses in monocytic cells and promotes their differentiation into mature dendritic cells. Here, we examined whether inhibition of heat shock protein 90 (HSP90) modulates these responses. Treatment with ganetespib, a selective HSP90 inhibitor, significantly reduced chemokine CCL2 expression, lowering monocytic cell migration. It also suppressed matrix metalloproteinase-9 (MMP-9) expression and attenuated the lipopolysaccharide (LPS) response otherwise amplified by 27OHChol. Furthermore, ganetespib decreased mature dendritic cell markers (CD80, CD83, CD88) and restored endocytic activity, indicating a less activated state. These changes suggest that HSP90 regulates 27OHChol-induced pro-inflammatory activation via its client proteins. To explore this mechanism, we examined the phosphorylation status of signaling proteins. 27OHChol enhanced phosphorylation of Akt and its downstream targets, S6 and 4E-BP1 within the Akt/mTORC1 pathway. Ganetespib reduced total and phosphorylated Akt and 4E-BP1, and selectively inhibited S6 phosphorylation without altering total protein level. Collectively, these findings demonstrate that HSP90 inhibition by ganetespib mitigates 27OHChol-driven monocytic cell activation through suppression of the HSP90-Akt/mTORC1 axis. Targeting this pathway may provide a promising therapeutic strategy for metabolic inflammation associated with oxysterols.
Keywords: Akt/mTORC1; heat shock protein 90; 27-hydroxycholesterol; inflammation; monocytic cell activation Akt/mTORC1; heat shock protein 90; 27-hydroxycholesterol; inflammation; monocytic cell activation

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MDPI and ACS Style

Kim, J.; Kwon, M.; Park, D.; Kang, N.; Son, Y.; Baryawno, N.; Kim, B.S.; Yoon, S.; Oh, S.-O.; Lee, D.; et al. HSP90 Inhibition Disrupts 27-Hydroxycholesterol-Induced Inflammatory Signaling in Monocytic Cells. Int. J. Mol. Sci. 2025, 26, 9963. https://doi.org/10.3390/ijms26209963

AMA Style

Kim J, Kwon M, Park D, Kang N, Son Y, Baryawno N, Kim BS, Yoon S, Oh S-O, Lee D, et al. HSP90 Inhibition Disrupts 27-Hydroxycholesterol-Induced Inflammatory Signaling in Monocytic Cells. International Journal of Molecular Sciences. 2025; 26(20):9963. https://doi.org/10.3390/ijms26209963

Chicago/Turabian Style

Kim, Jaesung, Munju Kwon, Dongha Park, Nakyung Kang, Yonghae Son, Ninib Baryawno, Byoung Soo Kim, Sik Yoon, Sae-Ock Oh, Dongjun Lee, and et al. 2025. "HSP90 Inhibition Disrupts 27-Hydroxycholesterol-Induced Inflammatory Signaling in Monocytic Cells" International Journal of Molecular Sciences 26, no. 20: 9963. https://doi.org/10.3390/ijms26209963

APA Style

Kim, J., Kwon, M., Park, D., Kang, N., Son, Y., Baryawno, N., Kim, B. S., Yoon, S., Oh, S.-O., Lee, D., & Kim, K. (2025). HSP90 Inhibition Disrupts 27-Hydroxycholesterol-Induced Inflammatory Signaling in Monocytic Cells. International Journal of Molecular Sciences, 26(20), 9963. https://doi.org/10.3390/ijms26209963

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